Advances in Anti-Cancer Drugs

Immunosuppressants are emerging as promising candidates for cancer therapy with lower cytotoxicity compared to traditional chemotherapy drugs; yet, the intrinsic side effects such as immunosuppression remain a critical concern. Herein, we introduce a photoactivatable antitumor immunosuppressant called dmBODIPY-FTY720 (BF) that shows no cytotoxicity but can be temporally and locally activated by deep-red light illumination to induce tumor cell apoptosis. To further reduce potential side effects, we integrate BF with another classic photosensitizer called methylene blue (MB) that is activated under the same wavelength of deep-red light (>650 nm) and successfully establish a red-light-activatable AND Boolean logic gate through a mechanism that we found to be synergetic apoptotic induction. At further decreased dosages, deep-red light illumination does not induce cell death in the presence of either BF or MB, but significant cancer cell death is triggered in the presence of both drugs. Therefore, the dosage of BF is further reduced, which will be highly beneficial to minimize any potential side effects of BF. This AND-gated strategy has been successfully applied in vivo for effective suppression of hepatocarcinoma tumors in living mice. Full article

Bladder cancer is a urothelial malignancy. Bladder cancer starts in the urothelial cells lining the inside of the bladder. The 5-year recurrence rate for bladder cancer ranges from 31% to 78%, and the progression rate is approximately 45%. To treat bladder cancer, intravesical drug therapy is often used. Leonurus artemisia extract (LaE) was obtained from medicinal samples of Chinese motherwort Scientific Chinese Medicine; L. artemisia has various biological effects. This study investigated the impact of LaE on human bladder cancer cells (the BFTC-905 cell line) and the molecular mechanism underlying apoptosis resulting from the activation of cell signal transduction pathways in bladder cancer cells. A cell counting kit-8 (CCK-8) assay was used to determine the effect of LaE on cell growth. The effect of LaE on migration ability was observed using a wound healing assay. The effects of LaE on the cell cycle, reactive oxygen species production, and apoptosis were investigated. Western blot analysis detected apoptosis-related and mitogen-activated protein kinase signaling pathway-related protein concentrations. At non-toxic concentrations, LaE inhibited the proliferation of BFTC-905 cells in a concentration-dependent manner, and the half-maximal inhibitory concentration (IC50) was 24.08172 µg/µL. LaE impaired the migration ability of BFTC-905 cells. LaE arrested the cell cycle in the G1 and G0 phases, increased reactive oxygen species production, and induced apoptosis. LaE increased Bax and p-ERK concentrations and decreased Bcl-2, cleaved caspase-3, and p-p38 concentrations. No differences in PARP, C-PARP, vimentin, e-cadherin, p-JNK, or TNF-alpha concentrations were observed. These results suggest that LaE inhibits the proliferation of human bladder cancer cells. Moreover, the mitogen-activated protein kinase signaling pathway is involved in the inhibition of the proliferation of BFTC-905 cells. Full article

The objective of this study was to evaluate the effectiveness of organ-on-chip system investigating simultaneous cellular efficacy and real-time reactive oxygen species (ROS) occurrence of anticancer drug-loaded nanoparticles (NPs) using hepatocarcinoma cells (HepG2) chip system under static and hepatomimicking shear stress conditions (5 dyne/cm²). Then, the role of hepatomimetic shear stress exposed to HepG2 and drug solubility were compared. The highly soluble doxorubicin (DOX) and poorly soluble paclitaxel (PTX) were chosen. Fattigated NPs (AONs) were formed via self-assembly of amphiphilic albumin (HSA)-oleic acid conjugate (AOC). Then, drug-loaded AONs (DOX-AON or PTX-AON) were exposed to a serum-free HepG2 medium at 37 °C and 5% carbon dioxide for 24 h using a real-time ROS sensor chip-based microfluidic system. The cellular efficacy and simultaneous ROS occurrence of free drugs and drug-loaded AONs were compared. The cellular efficacy of drug-loaded AONs varied in a dose-dependent manner and were consistently correlated with real-time of ROS occurrence. Drug-loaded AONs increased the intracellular fluorescence intensity and decreased the cellular efficacy compared to free drugs under dynamic conditions. The half-maximal inhibitory concentration (IC₅₀) values of free DOX (13.4 μg/mL) and PTX (54.44 μg/mL) under static conditions decreased to 11.79 and 38.43 μg/mL, respectively, under dynamic conditions. Furthermore, DOX- and PTX-AONs showed highly decreased IC₅₀ values of 5.613 and 21.86 μg/mL, respectively, as compared to free drugs under dynamic conditions. It was evident that cellular efficacy and real-time ROS occurrence were well-correlated and highly dependent on the drug-loaded nanostructure, drug solubility and physiological shear stress. Full article

High-grade gliomas present a significant challenge in neuro-oncology because of their aggressive nature and resistance to current therapies. Boron neutron capture therapy (BNCT) is a potential treatment method; however, the boron used by the carrier compounds—such as 4-borono-L-phenylalanine (L-BPA)—have limitations. This study evaluated the use of boron-conjugated 4-iodophenylbutanamide (BC-IP), a novel boron compound in BNCT, for the treatment of glioma. Using in vitro drug exposure experiments and in vivo studies, we compared BC-IP and BPA, with a focus on boron uptake and retention characteristics. The results showed that although BC-IP had a lower boron uptake than BPA, it exhibited superior retention. Furthermore, despite lower boron accumulation in tumors, BNCT mediated by BC-IP showed significant survival improvement in glioma-bearing rats compared to controls (not treated animals and neutrons only). These results suggest that BC-IP, with its unique properties, may be an alternative boron carrier for BNCT. Further research is required to optimize this potential treatment modality, which could significantly contribute to advancing the treatment of high-grade gliomas. Full article

Hepatocellular carcinoma (HCC) is the second-largest cause of death among all cancer types. Many drugs have been used to treat the disease for a long time but have been mostly discontinued because of their side effects or the development of resistance in the patients with HCC. The administration of DZ orally is a great focus to address the clinical crisis. Daidzein (DZ) is a prominent isoflavone polyphenolic chemical found in soybeans and other leguminous plants. It has various pharmacological effects, including anti-inflammatory, antihemolytic, and antioxidant. This present study investigates the protective effect of DZ on chemically induced HCC in rat models. The DZ was administered orally four weeks before HCC induction and continued during treatment. Our study included four treatment groups: control (group 1, without any treatment), HCC-induced rats (group II), an HCC group treated with DZ at 20 mg/kg (group III), and an HCC group treated with DZ at 40 mg/kg (group IV). HCC rats showed elevation in all the HCC markers (AFP, GPC3, and VEGF), liver function markers (ALP, ALT, and AST), inflammatory markers (IL-6, TNF-α, and CRP), and lipid markers concomitant with a decrease in antioxidant enzymes and protein. However, groups III and IV demonstrated dose-dependent alleviation in the previous parameters resulting from HCC. In addition, the high dose of DZ reduces many hepatological changes in HCC rats. All study parameters improved with DZ administration. Due to its antioxidant and anti-inflammatory characteristics, DZ is a promising HCC treatment option for clinical use. Full article

A metastatic brain tumor is the most common type of malignancy in the central nervous system, which is one of the leading causes of death in patients with lung cancer. The purpose of this study is to evaluate the efficacy of a novel treatment for metastatic brain tumors with lung cancer using neural stem cells (NSCs), which encode rabbit carboxylesterase (rCE) and the secretion form of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). rCE and/or sTRAIL were transduced in immortalized human fetal NSCs, HB1.F3. The cytotoxic effects of the therapeutic cells on human lung cancer cells were evaluated in vitro with the ligands and decoy receptor expression for sTRAIL in the presence of CPT-11. Human NSCs encoding rCE (F3.CE and F3.CE.sTRAIL) significantly inhibited the growth of lung cancer cells in the presence of CPT-11 in vitro. Lung cancer cells were inoculated in immune-deficient mice, and therapeutic cells were transplanted systematically through intracardiac arterial injection and then treated with CPT-11. In resting state, DR4 expression in lung cancer cells and DcR1 in NSCs increased to 70% and 90% after CPT-11 addition, respectively. The volumes of the tumors in immune-deficient mice were reduced significantly in mice with F3.CE.sTRAIL transplantation and CPT-11 treatment. The survival was also significantly prolonged with treatment with F3.sTRAIL and F3.CE plus CPT-11 as well as F3.CE.sTRAIL plus CPT-11. NSCs transduced with rCE and sTRAIL genes showed a significant anti-cancer effect on brain metastatic lung cancer in vivo and in vitro, and the effect may be synergistic when rCE/CPT-11 and sTRAIL are combined. This stem-cell-based study using two therapeutic genes of different biological effects can be translatable to clinical application. Full article

Regardless of the presence or absence of specific diagnostic mutations, many cancer patients fail to respond to EGFR-targeted therapeutics, and a personalized approach is needed to identify putative (non)responders. We found previously that human peripheral blood and EGF can modulate the activities of EGFR-specific drugs on inhibiting clonogenity in model EGFR-positive A431 squamous carcinoma cells. Here, we report that human serum can dramatically abolish the cell growth rate inhibition by EGFR-specific drugs cetuximab and erlotinib. We show that this phenomenon is linked with derepression of drug-induced G1S cell cycle transition arrest. Furthermore, A431 cell growth inhibition by cetuximab, erlotinib, and EGF correlates with a decreased activity of ERK1/2 proteins. In turn, the EGF- and human serum-mediated rescue of drug-treated A431 cells restores ERK1/2 activity in functional tests. RNA sequencing revealed 1271 and 1566 differentially expressed genes (DEGs) in the presence of cetuximab and erlotinib, respectively. Erlotinib- and cetuximab-specific DEGs significantly overlapped. Interestingly, the expression of 100% and 75% of these DEGs restores to the no-drug level when EGF or a mixed human serum sample, respectively, is added along with cetuximab. In the case of erlotinib, EGF and human serum restore the expression of 39% and 83% of DEGs, respectively. We further assessed differential molecular pathway activation levels and propose that EGF/human serum-mediated A431 resistance to EGFR drugs can be largely explained by reactivation of the MAPK signaling cascade. Full article

Extracellular vesicle (EV) research has expanded substantially over the years. EVs have been identified in all living organisms and are produced and released as a means of intercellular communication or as a defense mechanism. Recently, nano-scaled vesicles were successfully isolated from edible plant sources. Plant-derived EVs, referred to here as phytosomes, are of a size reported to range between 30 nm and 120 nm in diameter, similar to small mammalian extracellular vesicles, and carry various bioactive molecules such as mRNA, proteins, miRNA and lipids. Due to the availability of many plants, phytosomes can be easily isolated on a large scale. The methods developed for EV isolation from mammalian cells have been successfully applied for isolation and purification of phytosomes. The therapeutic effects of phytosomes on different disease models, such as inflammation and autoimmune disease, have been reported, and a handful of studies have suggested their therapeutic effects on cancer diseases. Overall, the research on phytosomes is still in its infancy and requires more exploration. This review will narrate the anti-cancer activity and characteristics of phytosomes derived from edible plants as well as describe studies which have utilized phytosomes as drug delivery vehicles for cancer with the ultimate objective of significantly reducing the adverse effects associated with conventional therapeutic approaches. Full article

The Rho associated coiled-coil containing protein kinase (ROCK1 and ROCK2) and myotonic dystrophy-related Cdc-42 binding kinases (MRCKα and MRCKβ) are critical regulators of cell proliferation and cell plasticity, a process intimately involved in cancer cell migration and invasion. Previously, we reported the discovery of a novel small molecule (DJ4) selective multi-kinase inhibitor of ROCK1/2 and MRCKα/β. Herein, we further characterized the anti-proliferative and apoptotic effects of DJ4 in non-small cell lung cancer and triple-negative breast cancer cells. To further optimize the ROCK/MRCK inhibitory potency of DJ4, we generated a library of 27 analogs. Among the various structural modifications, we identified four additional active analogs with enhanced ROCK/MRCK inhibitory potency. The anti-proliferative and cell cycle inhibitory effects of the active analogs were examined in non-small cell lung cancer, breast cancer, and melanoma cell lines. The anti-proliferative effectiveness of DJ4 and the active analogs was further demonstrated against a wide array of cancer cell types using the NCI-60 human cancer cell line panel. Lastly, these new analogs were tested for anti-migratory effects in highly invasive MDA-MB-231 breast cancer cells. Together, our results demonstrate that selective inhibitors of ROCK1/2 (DJE4, DJ-Allyl) inhibited cell proliferation and induced cell cycle arrest at G2/M but were less effective in cell death induction compared with dual ROCK1/2 and MRCKα/β (DJ4 and DJ110). Full article

This systematic review and meta-analysis aims to evaluate the efficacy and safety of rechallenging advanced melanoma patients with BRAFi/MEKi. Seven studies, accounting for 400 patients, were included. Most patients received immunotherapy before the rechallenge, and 79% underwent rechallenge with the combination of BRAFi/MEKi. We found a median progression-free survival of 5 months and overall survival of 9.8 months. The one-year survival rate was 42.63%. Regarding response, ORR was 34% and DCR 65%. There were no new or unexpected safety concerns. Rechallenge with BRAFi/MEKi can improve outcomes in advanced melanoma patients with refractory disease. These findings have significant implications for clinical practice, particularly in the setting of progressive disease in later lines and limited treatment options. Full article

Squalene synthase (SQS) has emerged as a promising therapeutic target for various diseases, including cancers, owing to its pivotal role in the mevalonate pathway and the antioxidant properties of squalene. Primarily, SQS orchestrates the head-to-head condensation reaction, catalyzing the fusion of two farnesyl pyrophosphate molecules, leading to the formation of squalene, which has been depicted as a highly effective oxygen-scavenging agent in in vitro studies. Recent studies have depicted this isoprenoid as a protective layer against ferroptosis due to its potential regulation of lipid peroxidation, as well as its protection against oxidative damage. Therefore, beyond its fundamental function, recent investigations have unveiled additional roles for SQS as a regulator of lipid peroxidation and programmed cell death pathways, such as ferroptosis—a type of cell death characterized by elevated levels of lipid peroxide, one of the forms of reactive oxygen species (ROS), and intracellular iron concentration. Notably, thorough explorations have shed light on the distinctive features that set SQS apart from other members within the isoprenoid synthase superfamily. Its unique biochemical structure, intricately intertwined with its reaction mechanism, has garnered significant attention. Moreover, considerable evidence substantiates the significance of SQS in various disease contexts, and its intriguing association with ferroptosis and lipid peroxidation. The objective of this report is to analyze the existing literature comprehensively, corroborating these findings, and provide an up-to-date perspective on the current understanding of SQS as a prospective therapeutic target, as well as its intricate relationship with ferroptosis. This review aims to consolidate the knowledge surrounding SQS, thereby contributing to the broader comprehension of its potential implications in disease management and therapeutic interventions. Full article

Honey bee venom in its composition contains many biologically active peptides and enzymes that are effective in the fight against diseases of various etiologies. The history of the use of bee venom for medicinal purposes dates back thousands of years. There are many reports in the literature on the pharmacological properties of bee venom and/or its main components, e.g., anti-arthritic, anti-inflammatory, anti-microbial or neuroprotective properties. In addition, both crude venom and melittin exhibit cytotoxic activity against a wide range of tumor cells, with significant anti-metastatic activity in pre-clinical studies. Due to the constantly increasing incidence of cancer, the development of new therapeutic strategies in oncology is a particular challenge for modern medicine. A review paper discusses the various properties of bee venom with an emphasis on its anticancer properties. For this purpose, the PubMed database was searched, and publications related to “bee”, “venom”, “cancer” from the last 10 years were selected. Full article

Compounds that disrupt microtubule dynamics, such as colchicine, paclitaxel, or Vinca alkaloids, have been broadly used in biological studies and have found application in clinical anticancer medications. However, their main disadvantage is the lack of specificity towards cancerous cells, leading to severe side effects. In this paper, we report the first synthesis of 12 new visible light photoswitchable colchicine-based microtubule inhibitors AzoCols. Among the obtained compounds, two photoswitches showed light-dependent cytotoxicity in cancerous cell lines (HCT116 and MCF-7). The most promising compound displayed a nearly twofold increase in potency. Moreover, dissimilar inhibition of purified tubulin polymerisation in cell-free assay and light-dependent disruption of microtubule organisation visualised by immunofluorescence imaging sheds light on the mechanism of action as microtubule photoswitchable destabilisers. The presented results provide a foundation towards the synthesis and development of a novel class of photoswitchable colchicine-based microtubule polymerisation inhibitors. Full article

Basal cell carcinoma (BCC) represents the most common skin cancer and locally advanced BCC (laBCC) refers to an aggressive, large, infiltrative BCC that cannot be treated by surgery or radiotherapy. Sonidegib is a Hedghehog inhibitor (HHi) indicated for laBCC. This is a monocentric retrospective real-life study of laBCCs receiving Sonidegib treatment. Although Sonidegib is widely used, since its approval by Food and Drug Administration in 2015, only a limited number of real-life experiences have been reported. Eleven patients, including four patients diagnosed with Basal Cell Naevus syndrome, received treatment with Sonidegib for laBCCs. Seven (63.6%) patients experienced adverse events (AEs) but only three had to discontinue treatment and were therefore excluded from the following results. Four patients (50%) achieved complete clinical remission (CR); in all cases the remission was confirmed by biopsy. Partial response (PR) was found in three patients out of eight (37.5%). One patient out of eight (12.5%) showed a steady disease (SD). None of the patients showed signs of progression during treatment with HHi. Sonidegib showed the same efficacy in treating laBCCs as already seen in trials. All four patients suffering from Basal Cell Naevus syndrome achieved disease control by being treated with Sonidegib. Consequently, we strongly advise the joint management of laBCCs through a multidisciplinary team whenever feasible. Full article

Scutellaria multicaulis is a medicinal plant indigenous to Iran, Afghanistan, and Pakistan. It has been widely used as a prominent herb in traditional medicine for thousands of years. This plant is reported to contain baicalein, wogonin, and chrysin flavonoids, which are a significant group of chemical ingredients which can cure different diseases, such as breast cancer. S. multicaulis leaf extract was used for the bioreduction of silver nanoparticles (SmL-Ag-NPs), and their phytochemical contents and antioxidant, antibacterial, anti-proliferative, and apoptotic activity were evaluated. Optimal physicochemical properties of SmL-Ag-NPs were obtained by mixing 5% of leaf extract and 2 mM of aqueous AgNO₃ solution and confirmed by characterization studies including UV–visible spectrophotometry, Field Emission Scanning Electron Microscope (FE-SEM), Energy Dispersive X-ray (EDX), Dynamic Light Scattering (DLS), zeta potential, Thermogravimetric analysis (TGA), Surface-enhanced Raman spectroscopy (SERS), X-ray crystallography (XRD), and Fourier transform infrared (FTIR) Spectroscopy. SmL-Ag-NPs exhibited a higher content of total phenol and total flavonoid and potential antioxidant activity. SmL-Ag-NPs also demonstrated dose-dependent cytotoxicity against MDA-MB231 cell multiplication with an IC₅₀ value of 37.62 μg/mL through inducing cell apoptosis. Results show that SmL-Ag-NPs is effective at inhibiting the proliferation of MDA-MB231 cells compared to tamoxifen. This demonstrates that SmL-Ag-NPs could be a bio-friendly and safe strategy to develop new cancer therapies with a reduction in the adverse effects of chemotherapy in the near future. Full article

Poly (ADP-Ribose) polymerase inhibitors (PARPi) have emerged as a targeted therapy in cancer treatment with promising results in various types of cancer. This work aims to investigate the profile of adverse drug reactions (ADRs) associated with PARPi through the reports provided by the Eudravigilance (EV) database. We also intend to analyze the potential association of peripheral neuropathy to PARPi. Data on individual case safety reports (ICSRs) were obtained by accessing the European spontaneous reporting system via the EV website. A total of 12,762 ICSRs were collected from the EV database. Serious cases of nervous system disorders were analyzed providing strong evidence that peripheral neuropathy was reported in a higher frequency in patients treated with niraparib. Most cases reported a not recovered/not resolved outcome and involved drug withdrawal. However, several studies suggest that PARPi attenuate chemotherapy-induced painful neuropathy. Unexpected ADRs such as peripheral neuropathy may also occur, mostly in patients taking niraparib. Further pharmacovigilance studies should be conducted in this area to clarify with more precision the toxicity profile of these drugs. Full article

Glioblastoma multiforme (GB) and high-risk neuroblastoma (NB) are known to have poor therapeutic outcomes. As for most cancers, chemotherapy and radiotherapy are the current mainstay treatments for GB and NB. However, the known limitations of systemic toxicity, drug resistance, poor targeted delivery, and inability to access the blood-brain barrier (BBB), make these treatments less satisfactory. Other treatment options have been investigated in many studies in the literature, especially nutraceutical and naturopathic products, most of which have also been reported to be poorly effective against these cancer types. This necessitates the development of treatment strategies with the potential to cross the BBB and specifically target cancer cells. Compounds that target the endopeptidase, matrix metalloproteinase 2 (MMP-2), have been reported to offer therapeutic insights for GB and NB since MMP-2 is known to be over-expressed in these cancers and plays significant roles in such physiological processes as angiogenesis, metastasis, and cellular invasion. Chlorotoxin (CTX) is a promising 36-amino acid peptide isolated from the venom of the deathstalker scorpion, Leiurus quinquestriatus, demonstrating high selectivity and binding affinity to a broad-spectrum of cancers, especially GB and NB through specific molecular targets, including MMP-2. The favorable characteristics of nanoparticles (NPs) such as their small sizes, large surface area for active targeting, BBB permeability, etc. make CTX-functionalized NPs (CTX-NPs) promising diagnostic and therapeutic applications for addressing the many challenges associated with these cancers. CTX-NPs may function by improving diffusion through the BBB, enabling increased localization of chemotherapeutic and genotherapeutic drugs to diseased cells specifically, enhancing imaging modalities such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), optical imaging techniques, image-guided surgery, as well as improving the sensitization of radio-resistant cells to radiotherapy treatment. This review discusses the characteristics of GB and NB cancers, related treatment challenges as well as the potential of CTX and its functionalized NP formulations as targeting systems for diagnostic, therapeutic, and theranostic purposes. It also provides insights into the potential mechanisms through which CTX crosses the BBB to bind cancer cells and provides suggestions for the development and application of novel CTX-based formulations for the diagnosis and treatment of GB and NB in the future. Full article

In 2022, approximately 600,000 cancer deaths were expected; more than 50,000 of those deaths would be from colorectal cancer (CRC). The CRC mortality rate in the US has decreased in recent decades, with a 51% drop between 1976 and 2014. This drop is attributed, in part, to the tremendous therapeutic improvements, especially after the 2000s, in addition to increased social awareness regarding risk factors and diagnostic improvement. Five-fluorouracil, irinotecan, capecitabine, and later oxaliplatin were the mainstays of mCRC treatment from the 1960s to 2002. Since then, more than a dozen drugs have been approved for the disease, betting on a new chapter in medicine, precision oncology, which uses patient and tumor characteristics to guide the therapeutic choice. Thus, this review will summarize the current literature on targeted therapies, highlighting the molecular biomarkers involved and their pathways. Full article

Cisplatin is a common drug used to treat patients with oral squamous cell carcinoma. However, cisplatin-induced chemoresistance poses a major challenge to its clinical application. Our recent study has shown that anethole possesses an anti-oral cancer effect. In this study, we examined the combined effect of anethole and cisplatin on oral cancer therapy. Gingival cancer cells Ca9-22 were cultured in the presence of various concentrations of cisplatin with or without anethole. The cell viability/proliferation and cytotoxicity were evaluated, respectively, by MTT, Hoechst staining, and LDH assay, while colony formation was measured by crystal violet. Oral cancer cell migration was evaluated by the scratch method. Apoptosis, caspase activity, oxidative stress, MitoSOX, and mitochondrial membrane potential (ΔΨm) levels were evaluated by flow cytometry, and the inhibition of signaling pathways was investigated by Western blot. Our results show that anethole (3 µM) potentiates cisplatin-induced inhibition of cell proliferation and decreases the ΔΨm on Ca9-22 cells. Furthermore, drug combination was found to inhibit cell migration and enhanced cisplatin cytotoxicity. The combination of anethole and cisplatin potentiates cisplatin-induced oral cancer cell apoptosis through the activation of caspase, while we also found anethole and cisplatin to enhance the cisplatin-induced generation of reactive oxygen species (ROS) and mitochondrial stress. In addition, major cancer signaling pathways were inhibited by the combination of anethole and cisplatin such as MAPKase, beta-catenin, and NF-κB pathways. This study reports that the combination of anethole and cisplatin might provide a beneficial effect in enhancing the cisplatin cancer cell-killing effect, thus lowering the associated side effects. Full article

A deeper understanding of the communication mechanisms of tumor cells in a tumor microenvironment can improve the development of new therapeutic solutions, leading to a more personalized approach. Recently, the field of extracellular vesicles (EVs) has drawn attention due to their key role in intercellular communication. EVs are nano-sized lipid bilayer vesicles that are secreted by all types of cells and can function as intermediators of intercellular communication with the ability to transfer different cargo (proteins, nucleic acids, sugar…) types among cells. This role of EVs is essential in a cancer context as it can affect tumor promotion and progression and contribute to the pre-metastatic niche establishment. Therefore, scientists from basic, translational, and clinical research areas are currently researching EVs with great expectations due to their potential to be used as clinical biomarkers, which are useful for disease diagnosis, prognosis, patient follow-up, or even as vehicles for drug delivery due to their natural carrier nature. The application of EVs presents numerous advantages as drug delivery vehicles, namely their capacity to overcome natural barriers, their inherent cell-targeting properties, and their stability in the circulation. In this review, we highlight the distinctive features of EVs, their application as efficient drug delivery systems, and their clinical applications. Full article

Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (1–6) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of 1–6. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (5 and 6) were determined to be the most biologically potent, demonstrating GI₅₀ values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI₅₀ value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 1–6 in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy. Full article

Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with shorter five-year survival than other breast cancer subtypes, and lacks targeted and hormonal treatment strategies. The signal transducer and activator of transcription 3 (STAT3) signaling is up-regulated in various tumors, including TNBC, and plays a vital role in regulating the expression of multiple proliferation- and apoptosis-related genes. Results: By combining the unique structures of the natural compounds STA-21 and Aulosirazole with antitumor activities, we synthesized a class of novel isoxazoloquinone derivatives and showed that one of these compounds, ZSW, binds to the SH2 domain of STAT3, leading to decreased STAT3 expression and activation in TNBC cells. Furthermore, ZSW promotes STAT3 ubiquitination, inhibits the proliferation of TNBC cells in vitro, and attenuates tumor growth with manageable toxicities in vivo. ZSW also decreases the mammosphere formation of breast cancer stem cells (BCSCs) by inhibiting STAT3. Conclusions: We conclude that the novel isoxazoloquinone ZSW may be developed as a cancer therapeutic because it targets STAT3, thereby inhibiting the stemness of cancer cells. Full article

Encouraged by the significant cytotoxic activity of simple α-aminophosphonates, a molecular library comprising phosphonoylmethyl- and phosphinoylmethyl-α-aminophosphonates, a tris derivative, and N-acylated species was established. The promising aminophosphonate derivatives were subjected to a comparative structure–activity analysis. We evaluated 12 new aminophosphonate derivatives on tumor cell cultures of different tissue origins (skin, lung, breast, and prostate). Several derivatives showed pronounced, even selective cytostatic effects. According to IC₅₀ values, phosphinoylmethyl-aminophosphonate derivative 2e elicited a significant cytostatic effect on breast adenocarcinoma cells, but it was even more effective against prostatic carcinoma cells. Based on our data, these new compounds exhibited promising antitumor activity on different tumor types, and they might represent a new group of alternative chemotherapeutic agents. Full article

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001–September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator’s choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population. Full article

Phosphatidylinositol 3-kinase (PI3K) plays an important role in cell proliferation, survival, migration, and metabolism, and has become an effective target for cancer treatment. Meanwhile, inhibiting both PI3K and mammalian rapamycin receptor (mTOR) can simultaneously improve the efficiency of anti-tumor therapy. Herein, a series of 36 sulfonamide methoxypyridine derivatives with three different aromatic skeletons were synthesized as novel potent PI3K/mTOR dual inhibitors based on a scaffold hopping strategy. Enzyme inhibition assay and cell anti-proliferation assay were employed to assess all derivatives. Then, the effects of the most potent inhibitor on cell cycle and apoptosis were performed. Furthermore, the phosphorylation level of AKT, an important downstream effector of PI3K, was evaluated by Western blot assay. Finally, molecular docking was used to confirm the binding mode with PI3Kα and mTOR. Among them, 22c with the quinoline core showed strong PI3Kα kinase inhibitory activity (IC₅₀ = 0.22 nM) and mTOR kinase inhibitory activity (IC₅₀ = 23 nM). 22c also showed a strong proliferation inhibitory activity, both in MCF-7 cells (IC₅₀ = 130 nM) and HCT-116 cells (IC₅₀ = 20 nM). 22c could effectively cause cell cycle arrest in G0/G1 phase and induce apoptosis of HCT-116 cells. Western blot assay showed that 22c could decrease the phosphorylation of AKT at a low concentration. The results of the modeling docking study also confirmed the binding mode of 22c with PI3Kα and mTOR. Hence, 22c is a promising PI3K/mTOR dual inhibitor, which is worthy of further research in the area. Full article

Cantú syndrome (CS) is caused by the gain of function mutations in the ABCC9 and KCNJ8 genes encoding, respectively, for the sulfonylureas receptor type 2 (SUR2) and the inwardly rectifier potassium channel 6.1 (Kir6.1) of the ATP-sensitive potassium (KATP) channels. CS is a multi-organ condition with a cardiovascular phenotype, neuromuscular symptoms, and skeletal malformations. Glibenclamide has been proposed for use in CS, but even in animals, the drug is incompletely effective against severe mutations, including the Kir6.1^wt/V65M. Patch-clamp experiments showed that zoledronic acid (ZOL) fully reduced the whole-cell KATP currents in bone calvaria cells from wild type (WT/WT) and heterozygous Kir6.1^wt/V65MCS mice, with IC₅₀ for ZOL block < 1 nM in each case. ZOL fully reduced KATP current in excised patches in skeletal muscle fibers in WT/WT and CS mice, with IC₅₀ of 100 nM in each case. Interestingly, KATP currents in the bone of heterozygous SUR2^wt/A478V mice were less sensitive to ZOL inhibition, showing an IC₅₀ of ~500 nM and a slope of ~0.3. In homozygous SUR2^A478V/A478V cells, ZOL failed to fully inhibit the KATP currents, causing only ~35% inhibition at 100 μM, but was responsive to glibenclamide. ZOL reduced the KATP currents in Kir6.1^wt/VMCS mice in both skeletal muscle and bone cells but was not effective in the SUR2^[A478V] mice fibers. These data indicate a subunit specificity of ZOL action that is important for appropriate CS therapies. Full article

Due to their low immunogenicity, high biocompatibility and ready availability in large quantities, plant-derived vesicles extracts have attracted considerable interest as a novel nanomaterial in tumor therapy. Bitter melon, a medicinal and edible plant, has been reported to exhibit excellent antitumor effects. It is well-documented that breast cancer gravely endangers women’s health, and more effective therapeutic agents must be urgently explored. Therefore, we investigated whether bitter melon-derived vesicles extract (BMVE) has antitumor activity against breast cancer. Ultracentrifugation was used to isolate BMVE with a typical “cup-shaped” structure and an average size of approximately 147 nm from bitter melon juice. The experimental outcomes indicate that 4T1 breast cancer cells could efficiently internalize BMVE, which shows apparent anti-proliferative and migration-inhibiting effects. In addition, BMVE also possesses apoptosis-inducing effects on breast cancer cells, which were achieved by stimulating the production of reactive oxygen species (ROS) and disrupting mitochondrial function. Furthermore, BMVE could dramatically inhibit tumor growth in vivo with negligible adverse effects. In conclusion, BMVE exhibits a pronounced antitumor effect on 4T1 breast cancer cells, which has great potential for use in tumor therapy. Full article

Cdc20 is a promising drug target that plays an important role in the mid-anaphase process of cellular mitosis, and Apcin is the only reported core structure of the Cdc20-specific inhibitor. Some potent Apcin derivatives were obtained in our previous research, and a structure–activity relationship was determined. In this study, we designed and synthesized a series of ureido-based Apcin derivatives. The proliferation-inhibition experiments on four cancer-cell lines showed that ureido skeleton could promote the anti-proliferation activity of purine-substituted compounds, whereas the ureido analogues with pyrimidine substitutes showed no significant improvement in the inhibitory effect compared with the original ones. Further tests confirmed that ureido-based compounds can enhance the binding affinity to Cdc20 by increasing the levels of Cdc20 downstream proteins. Compound 27 revealed a remarkably antitumor activity pattern against Hela (IC₅₀ = 0.06 ± 0.02 μM) and potent binding affinity to Cdc20. Moreover, compound 20 induced caspase-dependent apoptosis and cell-cycle arrest at the G2/M phase, and compound 27 induced caspase-dependent apoptosis and promoted microtubule polymerization. Finally, a molecular-docking simulation was performed for compounds 20 and 27 to predict the potential ligand–protein interactions with the active sites of the Cdc20 proteins. Full article

Immunotherapy for cancer treatment has gained increased attention in recent years. Recently, our group reported the case of a patient with glioblastoma who underwent vaccination based on dendritic cells and experienced a strong Th1 immune response together with near-complete tumor remission. Here we report the results of a phase I/II prospective, non-controlled clinical trial with 37 patients harboring glioblastoma or grade 4 astrocytomas. At the time of first recurrence after surgery, patients began receiving monthly intradermal injections of allogenic DC-autologous tumor cell hybridomas. Overall survival, quality of life, and immunological profiles were assessed prospectively. Compared with patients in the Genomic Data Commons data bank, overall survival for vaccinated patients with glioblastoma was 27.6 ± 2.4 months (vs. 16.3 ± 0.7, log-rank p < 0.001, hazard ratio 0.53, 95%CI 0.36–0.78, p < 0.01), and it was 59.5 ± 15.9 for vaccinated astrocytoma grade 4 patients (vs. 19.8 ± 2.5, log-rank p < 0.05, hazard ratio 0.18, 95%CI 0.05–0.62, p < 0.01). Furthermore, seven vaccinated patients (two IDH-1-mutated and five wild type) remain alive at the time of this report (overall survival 47.9 months, SD 21.1, range: 25.4–78.6 months since diagnosis; and 34.2 months since recurrence, range: 17.8 to 40.7, SD 21.3). We believe that the data reported here can foster the improvement of treatment protocols for high-grade gliomas based on cellular immunotherapy. Full article

In primary central nervous system lymphoma, two-year progression-free survival rates of up to 63 percent have been reported for first-line autologous stem cell transplantation after conditioning with the thiotepa busulfan cyclophosphamide regimen. However, 11 percent of the patients died due to toxicity. Besides conventional survival, progression-free survival and treatment related mortality analyses, a competing-risk analysis was applied to our cohort of twenty-four consecutive patients with primary or secondary central nervous system lymphoma who underwent autologous stem cell transplantation after thiotepa busulfan cyclophosphamide conditioning. The two-year overall survival and progression-free survival rates were 78 percent and 65 percent, respectively. The treatment-related mortality rate was 21 percent. The competing risks analysis demonstrate that age 60 or over and the infusion of less than 4.6 × 106/kg CD34+ stem cells were significant adverse prognostic factors for overall survival. Autologous stem cell transplantation with thiotepa busulfan cyclophosphamide conditioning was associated with sustained remission and survival. Nevertheless, the intensive thiotepa busulfan cyclophosphamide conditioning regimen was highly toxic, especially in older patients. Thus, our results suggest that future studies should aim at identifying the subgroup of patients who will really benefit of the procedure and/or to reduce the toxicity of future conditioning regimen. Full article

Cancer is one of the major causes of mortality, globally. Cancerous cells invade normal cells and metastasize to distant sites with the help of the lymphatic system. There are several mechanisms involved in the development and progression of cancer. Several treatment strategies including the use of phytoconstituents have evolved and been practiced for better therapeutic outcomes against cancer. Fisetin is one such naturally derived flavone that offers numerous pharmacological benefits, i.e., antioxidant, anti-inflammatory, antiangiogenic, and anticancer properties. It inhibits the rapid growth, invasiveness, and metastasis of tumors by hindering the multiplication of cancer cells, and prompts apoptosis by avoiding cell division related to actuation of caspase-9 and caspase-8. However, its poor bioavailability associated with its extreme hydrophobicity hampers its clinical utility. The issues related to fisetin delivery can be addressed by adapting to the developmental aspects of nanomedicines, such as formulating it into lipid or polymer-based systems, including nanocochleates and liposomes. This review aims to provide in-depth information regarding fisetin as a potential candidate for anticancer therapy, its properties and various formulation strategies. Full article

The present research paper details the synthesis of novel ionic compounds based on triterpene acids (betulinic, oleanolic and ursolic), with these acids acting both as anions and connected through a spacer with various nitrogen-containing compounds (pyridine, piperidine, morpholine, pyrrolidine, triethylamine and dimethylethanolamine) and acting as a cation. Based on the latter, a large number of ionic compounds with various counterions (BF₄-, SbF₆-, PF₆-, CH₃COO-, C₆H₅SO₃-, m-C₆H₄(OH)COO- and CH₃CH(OH)COO-) have been synthesized. We studied the cytotoxicity of the synthesized compounds on the example of various tumor (Jurkat, K562, U937, HL60, A2780) and conditionally normal (HEK293) cell lines. IC50 was determined, and the influence of the structure and nature of the anion and cation on the antitumor activity was specified. Intracellular signaling, apoptosis induction and effects of the most active ionic compounds on the cell cycle and mitochondria have been discussed by applying modern methods of multiparametric enzyme immunoassay and flow cytometry. Full article

ICIs have been able to improve overall survival in advanced-stage lung cancer. The benefit of this therapy is limited in patients with poor ECOG PS. However, this scale is imprecise and can be influenced by different factors, such as frailty. Cancer patients have a high risk of frailty independently of age. In this observational, single-center, retrospective study, we investigated the effect of frailty on the effectiveness of pembrolizumab in first-line use in a cohort of 101 patients with metastatic NSCLC. Frailty was determined using a frailty score system developed by Sakakida et al. Univariate and multivariate analysis was performed to determine the prognostic role of frailty on OS and PFS. Median OS was significantly higher in patients with low frailty compared with intermediate and high frailty (23.8 vs. 7.0 and 1.8 months, respectively; p < 0.001). Median PFS was also significantly higher in patients with low frailty compared with intermediate and high frailty (10.5 vs. 3.9 and 1.6 months; p < 0.001, respectively). Frailty was the only variable that showed significant differences in OS and PFS. Multivariate analysis confirms frailty as an independent predictor of OS and PFS. Frailty assessment could help to select which patients are candidates for ICIs in NSCLC. Full article

Objective: In recent years, the anti-programmed cell death protein-1 and its ligand (PD-1/PD-L1) or combination therapies have been recommended as an alternative emerging choice of treatment for oncology patients. However, the efficacy and adverse events of different combination strategies for the treatment of tumors remain controversial. Methods: PubMed, Embase, Cochrane Library, the American Society of Clinical Oncology (ASCO), and the European Society of Medicine Oncology (ESMO) were searched from database inception until 16 February 2022. The endpoints of objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were analyzed from different treatment schemes and tumor types. The protocol was registered in PROSPERO (CRD42022328927). Results: This meta-analysis included forty-eight eligible studies. Combination therapy has improved ORR (RR = 1.40, p < 0.001), DCR (RR = 1.22, p < 0.001), and PFS (the median survival ratio (MSR) was estimated to be 1.475 p < 0.001) compared to anti-PD-1/PD-L1 but had no significant benefit on OS (MSR was estimated to be 1.086 p = 0.117). Besides, combination treatment strategies are more toxic in any grade AEs (RR = 1.13, p < 0.001) and grade 3–5 AEs (RR = 1.81, p < 0.001). Conclusions: Treatment with PD-1/PD-L1 inhibitors in combination with other antitumor therapies improve patients’ ORR, DCR, and PFS compared to anti-PD-1/PD-L1. However, it is regrettable that there is no benefit to OS and an increased risk of AEs in combinatorial therapies. Full article

Background: Aromatase inhibitors (AI) are widely used for treating hormone-sensitive breast cancer (BC). Obesity, however, due to aromatase-mediated androgen conversion into estradiol in the peripheral adipose tissue, might impair AI inhibitory capacity. We aimed at identifying a cut-off of body mass index (BMI) with significant prognostic impact, in a cohort of stage I-II BC patients on systemic adjuvant therapy with AI. Methods: we retrospectively evaluated routinely collected baseline parameters. The optimal BMI cut-off affecting disease-free survival (DFS) in AI-treated BC patients was identified through maximally selected rank statistics; non-linear association between BMI and DFS in the AI cohort was assessed by hazard-ratio-smoothed curve analysis using BMI as continuous variable. The impact of the BMI cut-off on survival outcomes was estimated through Kaplan–Meier plots, with log-rank test and hazard ratio estimation comparing patient subgroups. Results: A total of 319 BC patients under adjuvant endocrine therapy and/or adjuvant chemotherapy were included. Curve-fitting analysis showed that for a BMI cut-off >29 in AI-treated BC patients (n = 172), DFS was increasingly deteriorating and that the impact of BMI on 2-year DFS identified a cut-off specific only for the cohort of postmenopausal BC patients under adjuvant therapy with AI. Conclusion: in radically resected hormone-sensitive BC patients undergoing neoadjuvant or adjuvant chemotherapy and treated with AI, obesity represents a risk factor for recurrence, with a significantly reduced 2-year DFS. Full article

The encouraging effects of HER2-ADC in patients with HER2-low expression cancers indicated the classical classifications based on positive and negative HER2 might no longer be suitable. However, the biology and prognosis of colorectal cancer patients with different HER2 expression status were still not clear. This is a multi-center retrospective study that included patients with histologically confirmed colorectal cancer and determined HER2 status who received radical surgical resection. HER2 immunohistochemistry (IHC) 1+ and IHC 2+ groups were combined and defined as a HER2-low group because of the concordance of clinicopathological characteristics. As compared with the HER2-high group, both the HER2-zero and the HER2-low group had less tumor with perineural invasion (14.3%, 13.1% vs. 31.6%, p = 0.001 and p < 0.001), less stage III disease (41.8%, 39.9% vs. 56.1%, p = 0.044 and p = 0.022), more RAS/BRAF mutation (52.1%, 49.9% vs. 19.5%, p < 0.001 and p < 0.001) and better disease-free survival (DFS) (3y-DFS rate of 78.7%, 82.4% vs. 59.3%, p < 0.001 and p < 0.001). Multivariate analysis and propensity score matching also revealed that HER2-high expression was an independent prognostic factor of DFS. In conclusion, our study revealed that HER2-low colorectal cancer tumors are close to HER2-zero tumors, but different from HER2-high tumors. The routine examination of HER2 IHC is needed in early-stage colorectal cancer. Full article

There are six members of the transmembrane 4 superfamily (TM4SF) that have similar topology and sequence homology. Physiologically, they regulate tissue differentiation, signal transduction pathways, cellular activation, proliferation, motility, adhesion, and angiogenesis. Accumulating evidence has demonstrated, among six TM4SF members, the regulatory roles of transmembrane 4 L6 domain family members, particularly TM4SF1, TM4SF4, and TM4SF5, in cancer angiogenesis, progression, and chemoresistance. Hence, targeting derailed TM4SF for cancer therapy has become an emerging research area. As compared to others, this review aimed to present a focused insight and update on the biological roles of TM4SF1, TM4SF4, and TM4SF5 in the progression, metastasis, and chemoresistance of various cancers. Additionally, the mechanistic pathways, diagnostic and prognostic values, and the potential and efficacy of current anti-TM4SF antibody treatment were also deciphered. It also recommended the exploration of other interactive molecules to be implicated in cancer progression and chemoresistance, as well as potential therapeutic agents targeting TM4SF as future perspectives. Generally, these three TM4SF members interact with different integrins and receptors to significantly induce intracellular signaling and regulate the proliferation, migration, and invasion of cancer cells. Intriguingly, gene silencing or anti-TM4SF antibody could reverse their regulatory roles deciphered in different preclinical models. They also have prognostic and diagnostic value as their high expression was detected in clinical tissues and cells of various cancers. Hence, TM4SF1, TM4SF4, and TM4SF5 are promising therapeutic targets for different cancer types preclinically and deserve further investigation. Full article

A series of 12 compounds was designed and synthesized, based on 2-mercaptobenzoxazole derivatives containing either the substituted benzenes 4a–d, substituted isatins 5a–f, or heterocycles 6a–b. The in vitro antiproliferative activity of the compounds was evaluated against hepatocellular carcinoma (HepG2), mammary gland cancer (MCF-7), breast cancer (MDA-MB-231), and the epithelioid cervix carcinoma (HeLa) cancer cell lines. Compounds 4b, 4d, 5d, and 6b had the most potent antiproliferative activity, with IC₅₀ values ranging from 2.14 to 19.34 µM, compared to the reference drugs, doxorubicin and sunitinib. Compound 6b revealed a remarkably broad antitumor activity pattern against HepG2 (IC₅₀ 6.83 µM), MCF-7 (IC₅₀ 3.64 µM), MDA-MB-231 (IC₅₀ 2.14 µM), and HeLa (IC₅₀ 5.18 µM). In addition, compound 6b showed potent inhibitory activities against EGFR, HER2, VEGFR2, and the CDK2 protein kinase enzymes, with IC₅₀ values of 0.279, 0.224, 0.565, and 0.886 µM, respectively. Moreover, compound 6b induced caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Finally, a molecular docking simulation was performed for compound 6b to predict the potential ligand–protein interactions with the active sites of the EGFR, HER2, and VEGFR2 proteins. Full article

Berberine hydrochloride (BBR) could inhibit the proliferation, migration, and invasion of various cancer cells. As the only enzyme for the de novo synthesis of ribonucleotides, RRM2 is closely related to the development of tumorigenesis. However, not much is currently known about the functional roles of RRM2 in breast cancer (BRCA), and whether BBR regulates the migration and invasion of BRCA cells by regulating the expression of RRM2 remains to be determined. We study the effects of BBR on BRCA cell proliferation in vitro and tumorigenesis in vivo by using colony formation assays, EdU assays, and xenograft models. Transcriptome sequencing, the random forest algorithm, and KEGG analysis were utilized to explore the therapeutic target genes and relative pathways. The expression of RRM2 in BRCA patients was analyzed with The Cancer Genome Atlas (TCGA) dataset, the GEPIA website tool, the Gene Expression Omnibus (GEO) database, and the UALCAN database. The survival probability of BRCA patients could be predicted by survival curve and nomogram analysis. Molecular docking was used to explore the affinity between BBR and potential targets. Gain- and loss-of-function methods were employed to explore the biological process in RRM2 participants. We comprehensively investigated the pharmacological characteristics of BBR on BRCA cell lines and discovered that BBR could inhibit the proliferation of BRCA cells in vitro and in vivo. Combining transcriptome sequencing and KEGG analysis, we found that BBR mainly affected the biological behavior of BRCA cells via HIF-1α and AMPK signal pathways. Additionally, by using bioinformatics and molecular docking, we demonstrated that RRM2 plays an oncogenic role in BRCA samples and that it acts as the hub gene of BBR on BRCA cells. Knockdown and overexpression studies indicated that RRM2 promoted BRCA cell migration as well as invasion in vitro by affecting the epithelial-to-mesenchymal transition (EMT). Our study demonstrated the significance of BBR regulating HIF-1α and AMPK signaling pathways in BRCA cells. Moreover, we revealed the carcinogenic role and potential mechanism of RRM2 as a core regulatory factor of BBR in BRCA in controlling BRCA invasion, migration, and EMT, suggesting that RRM2 may be a therapeutic target and prognostic biomarker for BRCA therapy. Full article

Background Anaplastic thyroid cancer (ATC) is the greatest lethal thyroid neoplasm with a low incidence and lacks an effective treatment strategy and standardized treatment protocol. PLX3397 (Pexidartinib) is an FDA-approved multitarget tyrosine kinase inhibitor. The research is designed to explore the possible anti-proliferative activity of pexidartinib on ATC, as well as its related molecular mechanisms. Methods The cell viability was assessed by CCK-8, LDH release, colony formation, and EdU detection assays. Apoptosis and the alteration on cell cycle arrest were characterized by flow cytometry (FCM). ER stress was evaluated by immunofluorescence (IF). ROS levels were determined by flow cytometry. Western blot assays were conducted to evaluate changes in key molecules related to apoptosis and ER stress. The ATC xenografts model was established, and immunohistochemistry was performed to validate the anti-ATC effects of pexidartinib in vivo. Results Pexidartinib significantly inhibited ATC cell proliferation and induced apoptosis and cell cycle arrest. Moreover, pexidartinib potently induced ER stress and elevated ROS in ATC cells, and the apoptotic cells and ER stress in ATC after administration of pexidartinib could be reversed by an ER stress inhibitor and ROS scavenger, respectively. Furthermore, pexidartinib treatment induced Nrf2 accumulation in nuclei and reduced the interaction of Nrf2 with Keap-1, and knockdown of Nrf2 enhanced the anti-ATC effects of pexidartinib in vitro. In addition, pexidartinib significantly inhibited ATC xenograft growth and proliferation in vivo, and the combination of ML385, an Nrf2 inhibitor, potently enhanced the anti-ATC effects of pexidartinib in vivo. Conclusion Our findings suggest pexidartinib is a potential agent for treating ATC. Co-administration with an Nrf2 inhibitor is an effective synergistic strategy. Full article

Sanyin formula (SYF) is used as a complementary treatment for triple-negative breast cancer (TNBC). The purpose of this study was to identify the potential functional components and clarify the underlying molecular mechanisms of SYF in TNBC. High-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) was used to identify the main components of SYF extracts. Network pharmacology and bioinformatic analyses were carried out to identify potential candidate targets of SYF in TNBC. Cell proliferation was determined with a Celigo imaging cytometer. Wound-healing and Transwell assays were adopted to evaluate cell migration. A Transwell cell-invasion assay was performed with Matrigel-coated membranes. In vivo bioluminescence imaging (BLI) and pathological analyses illustrated the effect of SYF on cancer cell metastasis in tumour-bearing mice. The inhibitory mechanism of SYF was investigated via quantitative PCR (qPCR) and Western blotting. We found that 3,4-dihydroxyphenyllactic acid, kaempferol, p-coumaric acid, and vanillic acid may be the active components of SYF. Molecular docking confirmed that kaempferol, p-coumaric acid, vanillic acid, and 3,4-dihydroxyphenyllactic acid bound stably to proteins such as AKR1C3, MMPs, and STAT3. SYF extract suppressed TNBC cell proliferation, migration, invasion, and metastasis by inhibiting JAK/STAT3 signalling and then regulating downstream genes, such as MMP-2/MMP-9. SYF regulates the expression of genes involved in cell proliferation, migration, and invasion by regulating the JAK/STAT3 signalling pathway and finally inhibits tumour cell metastasis in TNBC. The present study clarifies the mechanism by which SYF inhibits TNBC metastasis and lays an experimental foundation for the continued clinical development of SYF targeting the JAK/STAT3 pathway. Full article

BOLD-100 (sodium trans-[tetrachlorobis(1H indazole)ruthenate(III)]) is a ruthenium-based anticancer compound currently in clinical development. The identification of cancer types that show increased sensitivity towards BOLD-100 can lead to improved developmental strategies. Sensitivity profiling can also identify mechanisms of action that are pertinent for the bioactivity of complex therapeutics. Sensitivity to BOLD-100 was measured in a 319-cancer-cell line panel spanning 24 tissues. BOLD-100’s sensitivity profile showed variation across the tissue lineages, including increased response in esophageal, bladder, and hematologic cancers. Multiple cancers, including esophageal, bile duct and colon cancer, had higher relative response to BOLD-100 than to cisplatin. Response to BOLD-100 showed only moderate correlation to anticancer compounds in the Genomics of Drug Sensitivity in Cancer (GDSC) database, as well as no clear theme in bioactivity of correlated hits, suggesting that BOLD-100 may have a differentiated therapeutic profile. The genomic modalities of cancer cell lines were modeled against the BOLD-100 sensitivity profile, which revealed that genes related to ribosomal processes were associated with sensitivity to BOLD-100. Machine learning modeling of the sensitivity profile to BOLD-100 and gene expression data provided moderative predictive value. These findings provide further mechanistic understanding around BOLD-100 and support its development for additional cancer types. Full article

Hypoxia reprograms cancer stem cells. Nur77, an orphan nuclear receptor, highly expresses and facilitates colorectal cancer (CRC) stemness and metastasis under a hypoxic microenvironment. However, safe and effective small molecules that target Nur77 for CSC depletion remain unexplored. Here, we report our identification of the ginsenoside compound K (CK) as a new ligand of Nur77. CK strongly inhibits hypoxia-induced CRC sphere formation and CSC phenotypes in a Nur77-dependent manner. Hypoxia induces an intriguing Nur77-Akt feed-forward loop, resulting in reinforced PI3K/Akt signaling that is druggable by targeting Nur77. CK directly binds and modulates Nur77 phosphorylation to block the Nur77-Akt activation loop by disassociating Nur77 from the p63-bound Dicer promoter. The transcription of Dicer that is silenced under a hypoxia microenvironment is thus reactivated by CK. Consequently, the expression and processing capability of microRNA let-7i-5p are significantly increased, which targets PIK3CA mRNA for decay. The in vivo results showed that CK suppresses cancer stemness and metastasis without causing significant adverse effects. Given that the majority of FDA-approved and currently clinically tested PI3K/Akt inhibitors are reversible ATP-competitive kinase antagonists, targeting Nur77 for PI3K/Akt inactivation may provide an alternative strategy to overcoming concerns about drug selectivity and safety. The mechanistic target identification provides a basis for exploring CK as a promising nutraceutical against CRC. Full article

Background: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (mBC). Methods: We performed a systematic search with a predefined search strategy in PubMed, Embase and Cochrane CENTRAL databases to perform a network meta-analysis and evaluate the relative efficacies of ET-based treatment regimens in HR+/HER2- mBC patients with different endocrine sensitivity statuses. The study was registered in the PROSPERO database (CRD42021235570). Results: A total of 47 trials (20,267 patients) were included. Analysis of progression-free survival (PFS) in endocrine therapy-sensitive (ETS) patients revealed cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) + fulvestrant 500 mg (Ful 500) (random effect (RE): hazard ratio (HR), 0.46; 95% credibility interval (CrI), 0.27–0.78; surface under the cumulative ranking curve (SUCRA), 0.93; fixed effect (FE): HR, 0.48; 95% CrI, 0.40–0.58; SUCRA, 0.99) to be the best therapy followed by CDK4/6i + aromatase inhibitors (AIs) (RE: HR, 0.53; 95% CrI, 0.40–0.72; SUCRA, 0.86; FE: HR, 0.54; 95% CrI, 0.48–0.61; SUCRA, 0.91). Chemotherapy followed by CDK4/6i + Ful 500 appears to be the most effective option for the endocrine therapy-resistant (ETR) group. Analysis of overall survival revealed CDK4/6i + Ful 500 (SUCRA: 0.99) and AKTi + Ful 500 (SUCRA: 0.87) to be the first-rank regimen for the ETS group and ETR groups, respectively. Conclusion: Our comprehensive analysis suggests that CDK4/6i combined with ETs may be the best treatment option in terms of PFS for ETS patients and chemotherapy for ETR patients with HR+/HER2- mBC. Different endocrine sensitivity statuses required various optimal treatment strategies, which may provide guidance for clinical practice. Full article

Background: In the ATLANTIS study, second-line lurbinectedin/doxorubicin did not improve overall survival (OS), however patients with a chemotherapy-free interval (CTFI) of ≥180 days had an improved progression free survival (PFS). The objective of this retrospective study was to identify the proportion of real-world small cell lung cancer (SCLC) patients who are suitable for lurbinectedin-based therapy based on these criteria. Methods: A retrospective study of all SCLC referred to BC Cancer between 2012 and 2017 was conducted. Patient demographics, staging, treatment, and survival data were collected retrospectively. Baseline characteristics were compared using descriptive statistics. OS was calculated using Kaplan–Meier curves. Statistically significant p-value was <0.05. Results: A total of 1048 patients were identified. Baseline characteristics: median age 68 years, 47% male, 61% current smoking status, 68% extensive disease. Best supportive care was received by 22%. First-line systemic therapy was platinum doublet for 71% of the population. Second-line systemic therapy was delivered to 22%. Of the 219 patients who received second-line systemic therapy after platinum doublet, 183 patients had a CTFI of ≥90 days and 107 patients had a CTFI of ≥180 days. Patients originally treated as limited stage disease, received platinum doublet as second line, received thoracic radiation (RT) or prophylactic cranial irradiation (PCI) were more likely to have a CTFI of ≥90 and ≥180 days. Conclusion: In our real-world SCLC population, only 21% of the SCLC population received second-line therapy after platinum doublet with 17% achieving CTFI of ≥90 days and 10% CTFI of ≥180 days. Based on this retrospective review, only a small fraction of platinum-treated patients would be preferentially offered lurbinectedin in the second-line setting. Full article

In recent years, a dynamic development of oncology has been observed, resulting from the increasingly frequent occurrence of neoplasms and therefore, increasing population of patients. The most effective form of therapy for cancer patients is complex multidisciplinary specialized disease management, including nephro-oncology care. Different forms of renal function impairment are frequently diagnosed in cancer patients. They are caused by different co-morbidities existing before starting the oncologic treatment as well as the direct undesirable effects of this therapy which may cause temporary or irreversible damage of the urinary system—especially kidneys. According to different therapeutic programs, in such cases the degree of renal damage is often crucial for the possibility of further anti-cancer treatment. Medical personnel responsible for delivering care to oncology patients should be properly educated on current methods of prevention and treatment of renal complications resulting from anti-cancer therapy. The development of oncologic medicines design, including especially immuno-oncological agents, obliges us to learn new patomechanisms determining potential adverse effects, including renal complications. This publication is focused on the most important undesirable nephrotoxic effects of the frequently used anti-cancer drugs. Full article

Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is unknown. Class I histone deacetylases (including HDAC1, 2, 3, and 8) are one of the major classes of the HDAC family and catalyze the removal of acetyl groups from lysine residues in histones and cellular proteins. Class I HDACs exhibit distinct cellular and subcellular expression patterns and are involved in many biological processes and diseases through diverse signaling pathways. However, the link between class I HDACs and uLMS is still being determined. In this study, we assessed the expression panel of Class I HDACs in uLMS and characterized the role and mechanism of class I HDACs in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that HDAC1, 2, and 3 are aberrantly upregulated in uLMS tissues compared to adjacent myometrium. Immunoblot analysis demonstrated that the expression levels of HDAC 1, 2, and 3 exhibited a graded increase from normal and benign to malignant uterine tumor cells. Furthermore, inhibition of HDACs with Class I HDACs inhibitor (Tucidinostat) decreased the uLMS proliferation in a dose-dependent manner. Notably, gene set enrichment analysis of differentially expressed genes (DEGs) revealed that inhibition of HDACs with Tucidinostat altered several critical pathways. Moreover, multiple epigenetic analyses suggested that Tucidinostat may alter the transcriptome via reprogramming the oncogenic epigenome and inducing the changes in microRNA-target interaction in uLMS cells. In the parallel study, we also determined the effect of DL-sulforaphane on the uLMS. Our study demonstrated the relevance of class I HDACs proteins in the pathogenesis of malignant uLMS. Further understanding the role and mechanism of HDACs in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer. Full article

Glioblastoma (GBM) is the most common and lethal malignant primary brain tumor. The standard treatment for GBM including surgical resection followed by radiation therapy and adjuvant chemotherapy with temozolomide remains unsatisfactory. In this study, we investigated the effects of the Aurora kinase inhibitor, TAK901, in GBM both in vitro and in vivo, and explored its key downstream targets. The effects of TAK901 were investigated using cell viability, cell apoptosis, live/dead, cell cycle, Transwell, 3D cell invasion, neuro-sphere, and self-renewal assays. Mechanistic studies were conducted using RNA-seq, lipid measurements, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western blotting. The in vivo efficacy of TAK901 was validated using orthotopic xenograft GBM mouse models. In both GBM cells and GSCs, TAK901 remarkably reduced cell viability, self-renewal, migration and invasion and induced apoptosis and cell cycle arrest. Treatment with TAK901 considerably inhibited GBM growth in vivo. RNA-seq and RT-qPCR analyses showed that TAK901 downregulated the expression and activation of SREBP1. Moreover, SREBP1 overexpression alleviated the TAK901-mediated suppression of cell viability and apoptosis in GBM cells. Our results provide evidence that TAK901 inhibits GBM growth by suppressing SREBP1-mediated lipid metabolism. Full article

The norbornene scaffold has arisen as a promising structure in medicinal chemistry due to its possible therapeutic application in cancer treatment. The development of norbornene-based derivatives as potential chemotherapeutic agents is attracting significant attention. Here, we report an unprecedented review on the recent advances of investigations into the antitumoral efficacy of different compounds, including the abovementioned bicyclic scaffold in their structure, in combination with chemotherapeutic agents or forming metal complexes. The impact that structural modifications to these bicyclic compounds have on the antitumoral properties and the mechanisms by which these norbornene derivatives act are discussed in this review. In addition, the use of norbornene, and its related compounds, encapsulation in nanosystems for its use in cancer therapies is here detailed. Full article

Metastasis, in which cancer cells migrate to other tissues and form new tumors, is a major cause of both cancer death and treatment failure. In a previous study, benproperine (Benp) was identified as a cancer cell migration inhibitor and an inhibitor of actin-related protein 2/3 complex subunit 2 (ARPC2). However, Benp is a racemic mixture, and which stereoisomer is the active isomer remains unclear. In this study, we found that S-Benp is an active isomer and inhibits the migration and invasion of cancer cells much more strongly than R-Benp, with no effect on normal cells. The metastasis inhibitory effect of S-Benp was also verified in an animal model. Validating that inhibitors bind to their targets in cells and tissues has been a very challenging task in drug discovery. The direct interactions between ARPC2 and S-Benp were verified by surface plasmon resonance analysis (SPR), a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). In the mutant study with ARPC2^F225A cells, S-Benp did not bind to ARPC2^F225A according to CETSA and DARTS. Furthermore, we validated that S-Benp colocalized with ARPC2 in cancer cells and directly bound to ARPC2 in tumor tissues using Cy3-conjugated S-Benp according to CETSA. Finally, actin polymerization assays and immunocytochemistry showed that S-Benp suppressed actin remodeling such as lamellipodium formation. Taken together, our data suggest that S-Benp is an active stereoisomer of Benp and a potential metastasis inhibitor via ARPC2 binding. Full article

This prospective study investigated the impact of cabozantinib exposure on proteinuria and muscle toxicity, in a cohort of 14 Japanese patients with unresectable hepatocellular carcinoma (uHCC). We measured the trough concentration of cabozantinib (C_trough) weekly for 6 weeks after starting treatment. Although the initial dose was less than 60 mg in most cases, dose interruption occurred in 79%, primarily because of proteinuria and/or malaise. The median and coefficient of variation of maximum C_trough at 7–42 d were 929.0 ng/mL and 59.2%, respectively. The urinary protein-to-creatinine ratio (UPCR), serum creatine kinase, and serum aldolase values were all significantly elevated following treatment. Moreover, maximum changes in serum creatine kinase and aldolase were significantly associated with maximum C_trough (r = 0.736, p < 0.01; r = 0.798, p < 0.001; respectively). Receiver operating characteristic (ROC) curve analysis showed that changes in serum creatine kinase ≥70.5 U/L and aldolase ≥6.1 U/L from baseline relatively accurately predicted inclusion in the high-maximum C_trough (≥929.0 ng/mL) group, with an area under the ROC of 0.929 and 0.833, respectively. Measurement of serum creatine kinase and aldolase may increase the clinical usefulness of cabozantinib treatment for uHCC and help alleviate difficulties with dose adjustments. Full article

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with early metastatic potential. The standard-of-care treatment has not changed in years. Recent studies report improved progression-free survival (PFS) and overall survival (OS) with combined ICI and chemotherapy in ES-SCLC. We conducted a systematic review and meta-analysis to assess the magnitude of survival benefits. We searched MEDLINE, EMBASE, and Cochrane between 1 January 2010 and 15 July 2022 and conference proceedings from 2018 to 2022, for randomised controlled trials, evaluating chemo-ICI compared with platinum-doublet chemotherapy in untreated ES-SCLC. Outcomes assessed were PFS, OS, objective response rate (ORR), duration of response (DoR), toxicity, and health-related quality of life (HRQoL). The search identified 8061 studies, with 8 (56 publications) included in the final analysis. PFS and OS were significantly improved for patients randomised to chemo-ICI (PFS hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.70–0.80) and (OS HR 0.79, 95% CI 0.73–0.85). Subgroup analysis demonstrated a differential effect between PD-1/PD-L1 and CTLA-4 inhibitors. There was no difference in ORR and DoR. All-grade adverse events (RR 1.06, 95% CI 1.00–1.12) were similar. The addition of ICI to chemotherapy in untreated ES-SCLC results in a 22% risk reduction in death, and a 25% risk reduction in disease progression with a minimal increase in toxicity. These improvements are modest but represent progress beyond the standard of care. Full article

Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of cancers that had a significant increase in annual incidence in the last decade. They can be divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Poorly differentiated NECs are aggressive forms of cancers with limited therapeutic options. The first line treatment of metastatic poorly differentiated NECs is similar to small cell lung cancer, with cytotoxic chemotherapy (etoposide plus platinum). Patients who progress have limited therapeutic options and poor overall survival, calling for other novel agents to combat this deadly disease. Therefore, in this article, we summarized the effects of a novel component, Thymoquinone (TQ, C10H12O2), which is the main bioactive component of the black seed (Nigella sativa, Ranunculaceae family), plus immunotherapy in case series of patients with refractory metastatic extra-pulmonary NEC (EP-NEC) and one case of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). Methods: We report the effect of TQ plus dual immune checkpoint inhibitors (nivolumab plus ipilimumab) in four patients with poorly differentiated gastrointestinal Ep-NEC and MiNEN who progressed on cytotoxic chemotherapy. Results: This is the first case series to report the clinical activity of TQ plus dual immune checkpoint inhibitors (nivolumab plus ipilimumab) in patients with refractory metastatic EP-NEC. The four patients showed benefits with the combined regimen TQ plus dual ICPIs with durable response and exceeded the two years of progression-free survival. None of the four patients experienced significant toxicity, and all of them showed improvement in quality of life. Conclusion: The reported clinical courses suggest that combined TQ plus ICPIs is a potential promising regimen for refractory EP-NEC and MiNEN that deserves further prospective investigation. Full article

Immune checkpoint inhibitors (ICIs) therapy has been successfully utilized in the treatment of multiple tumors, but only a fraction of patients with gastric cancer (GC) could greatly benefit from it. A recent study has shown that the tumor microenvironment (TME) can greatly affect the effect of immunotherapy in GC. In this study, we established a novel immune risk signature (IRS) for prognosis and predicting response to ICIs in GC based on the TCGA-STAD dataset. Characterization of the TME was explored and further validated to reveal the underlying survival mechanisms and the potential therapeutic targets of GC. The GC patients were stratified into high- and low-risk groups based on the IRS. Patients in the high-risk group, associated with poorer outcomes, were characterized by significantly higher immune function. Further analysis showed higher T cell immune dysfunction and probability of potential immune escape. In vivo, we detected the expressions of SERPINE1 by the quantitative real-time polymerase chain reaction (qPCR)in tumor tissues and adjacent normal tissues. In vitro, knockdown of SERPINE1 significantly attenuated malignant biological behaviors of tumor cells in GC. Our signature can effectively predict the prognosis and response to immunotherapy in patients with GC. Full article

About 30 years ago, the first clinical trials of the safety and efficacy of recombinant interferon-α2 (rIFN-α2) were performed. Since then, several single-arm studies have shown rIFN-α2 to be a highly potent anticancer agent against several cancer types. Unfortunately, however, a high toxicity profile in early studies with rIFN-α2 -among other reasons likely due to the high dosages being used-disqualified rIFN-α2, which was accordingly replaced with competitive drugs that might at first glance look more attractive to clinicians. Later, pegylated IFN-α2a (Pegasys) and pegylated IFN-α2b (PegIntron) were introduced, which have since been reported to be better tolerated due to reduced toxicity. Today, treatment with rIFN-α2 is virtually outdated in non-hematological cancers, where other immunotherapies—e.g., immune-checkpoint inhibitors—are routinely used in several cancer types and are being intensively investigated in others, either as monotherapy or in combination with immunomodulatory agents, although only rarely in combination with rIFN-α2. Within the hematological malignancies, rIFN-α2 has been used off-label for decades in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs)—i.e., essential thrombocythemia, polycythemia vera, and myelofibrosis—and in recent years rIFN-α2 has been revived with the marketing of ropeginterferon-α2b (Besremi) for the treatment of polycythemia vera patients. Additionally, rIFN-α2 has been revived for the treatment of chronic myelogenous leukemia in combination with tyrosine kinase inhibitors. Another rIFN formulation-recombinant interferon-β (rIFN-β)—has been used for decades in the treatment of multiple sclerosis but has never been studied as a potential agent to be used in patients with MPNs, although several studies and reviews have repeatedly described rIFN-β as an effective anticancer agent as well. In this paper, we describe the rationales and perspectives for launching studies on the safety and efficacy of rIFN-β in patients with MPNs. Full article

M1 phenotype macrophages have anticancer characteristics, whereas M2 phenotype macrophages promote tumor growth and metastasis. A higher M1/M2 ratio, therefore, has a beneficial effect on the tumor immune microenvironment, thereby inhibiting tumor growth. The natural alkaloid curcumin is found to have anticancer properties. However, the mechanism remains unclear. In this study, a cell co-culture system and M2 macrophage model were used to evaluate the effects of curcumin on tumor-associated macrophage (TAM) phenotypes. Our results demonstrate that curcumin reprogrammed the M2 macrophages by reducing the level of anti-inflammatory cytokines (TGF-β, Arg-1, and IL-10) and an M2 surface marker (CD206) induced by Cal27 cells or IL-4, as well as upregulating proinflammatory cytokines (TNF-α, iNOS, and IL-6) and an M1 surface marker (CD86). The in vitro assays suggested that curcumin treatment suppressed the migration and invasion of the Cal27 cells induced by the M2-like macrophages. Mechanistically, the repolarization of TAMs may be attributed to the inhibition of monoamine oxidase A (MAO-A)/STAT6 signaling after curcumin treatment. Collectively, our results show that the anticancer effects of curcumin could be explained by reprogramming TAMs from a protumor phenotype towards an antitumor phenotype. Full article

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists. Full article

Approximately 20% of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relapse or are refractory to chemotherapy despite the low frequency of TP53 mutations. The nucleolar stress response is a P53-activating mechanism via MDM2 inhibition by ribosomal protein L11 (RPL11). We analyzed the role of the nucleolar stress response using BCP-ALL cell lines and patient samples by drug sensitivity tests, Western blotting, and reverse transcription polymerase chain reaction. We revealed that the nucleolar stress response works properly in TP53 wild-type human BCP-ALL cell lines. Next, we found that 6-mercaptopurine, methotrexate, daunorubicin, and cytarabine had anti-leukemic effects via the nucleolar stress response within BCP-ALL treatment. Comparing the samples at onset and relapse in children with BCP-ALL, RPL11 mRNA expression decreased at relapse in seven of nine cases. Furthermore, leukemia cells with relapse acquired resistance to these four drugs and suppressed P53 and RPL11 expression. Our findings suggest that the nucleolar stress response is a novel anti-leukemia mechanism in BCP-ALL. As these four drugs are key therapeutics for BCP-ALL treatment, dysfunction of the nucleolar stress response may be related to clinical relapse or refractoriness. Nucleolar stress response may be a target to predict and improve the chemotherapy effect for pediatric BCP-ALL. Full article

Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (¹⁰B) nuclei that have entered tumor cells to produce highly linear energy transfer (LET) alpha particles and recoil ⁷Li nuclei (¹⁰B [n, α] ⁷Li). Therefore, the most important part in BNCT is to selectively deliver a large number of ¹⁰B to tumor cells and only a small amount to normal tissue. So far, BNCT has been used in more than 2000 cases worldwide, and the efficacy of BNCT in the treatment of head and neck cancer, malignant meningioma, melanoma and hepatocellular carcinoma has been confirmed. We collected and collated clinical studies of second-generation boron delivery agents. The combination of different drugs, the mode of administration, and the combination of multiple treatments have an important impact on patient survival. We summarized the critical issues that must be addressed, with the hope that the next generation of boron delivery agents will overcome these challenges. Full article

Autophagy is a highly conserved metabolic pathway via which unwanted intracellular materials, such as unfolded proteins or damaged organelles, are digested. It is activated in response to conditions of oxidative stress or starvation, and is essential for the maintenance of cellular homeostasis and other vital functions, such as differentiation, cell death, and the cell cycle. Therefore, autophagy plays an important role in the initiation and progression of tumors, including hematological malignancies, where damaged autophagy during hematopoiesis can cause malignant transformation and increase cell proliferation. Over the last decade, the importance of autophagy in response to standard pharmacological treatment of hematological tumors has been observed, revealing completely opposite roles depending on the tumor type and stage. Thus, autophagy can promote tumor survival by attenuating the cellular damage caused by drugs and/or stabilizing oncogenic proteins, but can also have an antitumoral effect due to autophagic cell death. Therefore, autophagy-based strategies must depend on the context to create specific and safe combination therapies that could contribute to improved clinical outcomes. In this review, we describe the process of autophagy and its role on hematopoiesis, and we highlight recent research investigating its role as a potential therapeutic target in hematological malignancies. The findings suggest that genetic variants within autophagy-related genes modulate the risk of developing hemopathies, as well as patient survival. Full article

A phase I study evaluated the safety, tolerability, and maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of FCN-437c, a novel, orally available cyclin-dependent kinase inhibitor (CDK4/6i), in participants with advanced/metastatic solid tumors (aSTs). FCN-437c was escalated from 50 mg (once daily [QD] on days 1–21 of 28-day cycles) to the MTD/RP2D. In the dose-expansion phase, patients with CDK4/6i-treated breast cancer, or KRAS-mutant (KRAS^mut) non-small-cell lung cancer (NSCLC) received the MTD. Twenty-two patients were enrolled. The most common tumors in the dose-escalation phase (n = 15) were breast, colorectal, and lung (each n = 4 [27.3%]). The dose-expansion phase included five (71.4%) patients with breast cancer and two (28.6%) with KRAS^mut NSCLC. Twenty (90.9%) participants experienced FCN-437c–related adverse events. Dose-limiting toxicities occurred in two (33.3%) participants (200-mg dose, dose-escalation phase): grade 3 neutropenia and grade 4 neutrophil count decreased. Due to toxicities reported at 150 mg QD, the MTD was de-escalated to 100 mg QD. One (4.5%) participant (KRAS^mut NSCLC, 100-mg dose) achieved a partial response lasting 724+ days, and five (22.7%) had stable disease lasting 56+ days. In conclusion, FCN-437c was well tolerated with encouraging signs of antitumor activity and disease control. Further exploration of FCN-437c in aSTs is warranted. Full article

Shikonin is a naphthoquinone compound extracted from Chinese comfrey for treating cancer. However, there are few reports on its research on vertebrate tissue regeneration. Zebrafish is an ideal model for studying organ regeneration. In this study, we found that 3-dpf of zebrafish larvae exposed to shikonin at concentrations of 0.2, 0.3, and 0.4 mg/L showed increasingly inhibited regeneration of the tail fin. Immunohistochemical staining showed that shikonin exposure from 6 to 12 hpa increased the number of apoptotic cells in the caudal fin wound of larvae and decreased the number of proliferating cells. Shikonin exposure was found to up-regulate oxidative stress, increase ROS levels, and reduce neutrophil recruitment in the early stage of wound repair. Moreover, shikonin exposure caused disordered expression of fin regeneration blastemal-related genes. The use of astaxanthin to down-regulate oxidative stress was found to significantly reduce the inhibition of caudal fin regeneration. Mixed exposure of AMPK inhibitors or fullerenes (C60) with shikonin also showed the similar rescue effect. Collectively, our study showed that shikonin inhibited fin regeneration in zebrafish larvae by the upregulation of oxidative stress level and AMPK signaling pathway. This research provides valuable information on the mechanism of action of shikonin for its safe application. Full article

A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5–40 and sulfinyl 41–62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63–82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53−/− (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC₅₀) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates. Full article

Some chemotherapeutic agents have been found to enhance antitumor immunity by inducing immunogenic cell death (ICD). The combination of disulfiram (DSF) and copper (Cu) has demonstrated anti-tumor effects in a range of malignancies including hepatocellular carcinoma (HCC). However, the potential of DSF/Cu as an ICD inducer and whether it can enhance the efficacy of the immune checkpoint blockade in HCC remains unknown. Here, we showed that DSF/Cu-treated HCC cells exhibited characteristics of ICD in vitro, such as calreticulin (CRT) exposure, ATP secretion, and high mobility group box 1 (HMGB1) release. DSF/Cu-treated HCC cells elicited significant immune memory in a vaccination assay. DSF/Cu treatment promoted dendritic cell activation and maturation. The combination of DSF/Cu and CD47 blockade further facilitated DC maturation and subsequently enhanced CD8⁺ T cell cytotoxicity. Mechanically, DSF/Cu promoted the nuclear accumulation and aggregation of nuclear protein localization protein 4 (NPL4) to inhibit the ubiquitin-proteasome system; thus, inducing endoplasmic reticulum (ER) stress. The inhibition of NPL4 induced ICD-associated damage-associated molecular patterns. Collectively, our findings demonstrated that DSF/Cu-induced ICD-mediated immune activation in HCC enhanced the efficacy of CD47 blockade. Full article

Acute myeloid leukaemia (AML) is one of the most common types of haematopoietic malignancy. Ribonucleotide reductase (RNR) is a key enzyme required for DNA synthesis and cell proliferation, and its small subunit RRM2 plays a key role for the enzymatic activity. We predicted monobenzone (MB) as a potential RRM2 target compound based on the crystal structure of RRM2. In vitro, MB inhibited recombinant RNR activity (IC50 = 0.25 μM). Microscale thermophoresis indicated that MB inhibited RNR activity by binding to RRM2. MB inhibited cell proliferation (MTT IC50 = 6–18 μM) and caused dose-dependent DNA synthesis inhibition, cell cycle arrest, and apoptosis in AML cells. The cell cycle arrest was reversed by the addition of deoxyribonucleoside triphosphates precursors, suggesting that RNR was the intracellular target of the compound. Moreover, MB overcame drug resistance to the common AML drugs cytarabine and doxorubicin, and treatment with the combination of MB and the Bcl-2 inhibitor ABT-737 exerted a synergistic inhibitory effect. Finally, the nude mice xenografts study indicated that MB administration produced a significant inhibitory effect on AML growth with relatively weak toxicity. Thus, we propose that MB has the potential as a novel anti-AML therapeutic agent in the future. Full article

Due to the obstruction and heterogeneity of the blood-brain barrier, the clinical treatment of glioma has been extremely difficult. Isoliquiritigenin (ISL) exhibits antitumor effects, but its low solubility and bioavailability limit its application potential. Herein, we established a nanoscale hybrid membrane-derived system composed of erythrocytes and tumor cells. By encapsulating ISL in hybrid membrane nanoparticles, ISL is expected to be enhanced for the targeting and long-circulation in gliomas therapy. We fused erythrocytes with human glioma cells U251 and extracted the fusion membrane via hypotension, termed as hybrid membrane (HM). HM-camouflaged ISL nanoparticles (ISL@HM NPs) were prepared and featured with FT-IR, SEM, TEM, and DLS particle analysis. As the results concluded, the ISL active pharmaceutical ingredients (APIs) were successfully encapsulated with HM membranes, and the NPs loading efficiency was 38.9 ± 2.99% under maximum entrapment efficiency. By comparing the IC50 of free ISL and NPs, we verified that the solubility and antitumor effect of NPs was markedly enhanced. We also investigated the mechanism of the antitumor effect of ISL@HM NPs, which revealed a marked inhibition of tumor cell proliferation and promotion of senescence and apoptosis of tumor cells of the formulation. In addition, the FSC and WB results examined the effects of different concentrations of ISL@HM NPs on tumor cell disruption and apoptotic protein expression. Finally, it can be concluded that hybridized membrane-derived nanoparticles could prominently increase the solubility of insoluble materials (as ISL), and also enhance its targeting and antitumor effect. Full article

Death receptor 5 (DR5) is a membrane protein that mediates exogenous apoptosis. Based on its function, it is considered to be a target for the treatment of cancers including prostate cancer. It is encouraging to note that a number of drugs targeting DR5 are now progressing to different stages of clinical trial studies. We collected 38 active compounds that could produce anti-prostate-cancer effects by modulating DR5, 28 of which were natural compounds and 10 of which were synthetic compounds. In addition, 6 clinically used chemotherapeutic agents have also been shown to promote DR5 expression and thus exert apoptosis-inducing effects in prostate cancer cells. These compounds promote the expression of DR5, thereby enhancing its function in inducing apoptosis. When these compounds were used in combination with the natural ligand of DR5, the number of apoptotic cells was significantly increased. These compounds are all promising for development as anti-prostate-cancer drugs, while most of these compounds are currently being evaluated for their anti-prostate-cancer effects at the cellular level and in animal studies. A great deal of more in-depth research is needed to evaluate whether they can be developed as drugs. We collected literature reports on small molecules against prostate cancer through modulation of DR5 to understand the current dynamics in this field and to evaluate the prospects of small molecules against prostate cancer through modulation of DR5. Full article

Background: Arginases play essential roles in metabolic pathways, determining the fitness of both immune and tumour cells. Along with the previously validated role of ARG1 in cancer, the particular significance of ARG2 as a therapeutic target has emerged as its levels correlate with malignant phenotype and poor prognosis. These observations unveil arginases, and specifically ARG2, as well-validated and promising therapeutic targets. OATD-02, a new boronic acid derivative, is the only dual inhibitor, which can address the benefits of pharmacological inhibition of arginase 1 and 2 in cancer. Methods: The inhibitory activity of OATD-02 was determined using recombinant ARG1 and ARG2, as well as in a cellular system using primary hepatocytes and macrophages. In vivo antitumor activity was determined in syngeneic models of colorectal and kidney carcinomas (CT26 and Renca, respectively), as well as in an ARG2-dependent xenograft model of leukaemia (K562). Results: OATD-02 was shown to be a potent dual (ARG1/ARG2) arginase inhibitor with a cellular activity necessary for targeting ARG2. Compared to a reference inhibitor with predominant extracellular activity towards ARG1, we have shown improved and statistically significant antitumor efficacy in the CT26 model and an immunomodulatory effect reflected by Treg inhibition in the Renca model. Importantly, OATD-02 had a superior activity when combined with other immunotherapeutics. Finally, OATD-02 effectively inhibited the proliferation of human K562 leukemic cells both in vitro and in vivo. Conclusions: OATD-02 is a potent small-molecule arginase inhibitor with optimal drug-like properties, including PK/PD profile. Excellent activity against intracellular ARG2 significantly distinguishes OATD-02 from other arginase inhibitors. OATD-02 represents a very promising drug candidate for the combined treatment of tumours, and is the only pharmacological tool that can effectively address the benefits of ARG1/ARG2 inhibition. OATD-02 will enter clinical trials in cancer patients in 2022. Full article

Adverse reactions during and shortly after infusing asparaginase for the treatment of acute lymphoblastic leukemia can increase in severity with later doses, limiting further use and increasing relapse risk. Although asparaginase is associated with hyperammonemia, the magnitude of the increase in serum ammonia immediately after the infusion and in response to multiple infusions has not been examined. The concurrence of hyperammonemia and infusion reactions was studied using weaned juvenile pigs that received 12 infusions of Erwinia asparaginase (Erwinase; 1250 U/kg) over 28 days, with two 5-day recovery periods without asparaginase after the eighth and eleventh doses. Infusion reactions and prolonged hyperammonemia (>50 µM ammonia 48 h after the infusion) began after the fourth dose and increased with later doses. Dense sampling for 60 min revealed an acute phase of hyperammonemia that peaked within 20 min after starting the first infusion (298 + 62 µM) and lasted less than 1 h, without apparent symptoms. A pronounced acute hyperammonemia after the final infusion (1260 + 250 µM) coincided with severe symptoms and one mortality during the infusion. The previously unrecognized acute phase of hyperammonemia associated with asparaginase infusion coincides with infusion reactions. The juvenile pig is a translational animal model for understanding the causes of acute and chronic hyperammonemia, differentiating from hypersensitivity reactions, and for improving infusion protocols to reduce acute hyperammonemia and to allow the continued use of asparaginase. Full article

Non–small-cell lung cancer (NSCLC) is one of the most fatal malignant tumors harmful to human health. Previous studies report that Platycodin D (PD) exhibits anti-tumor effects in multiple human cancers, including NSCLC, but the underlying mechanisms are largely unknown. Accumulating evidence indicates that non-coding RNAs (ncRNAs) participate in NSCLC disease progression, but the link between PD and the ncRNAs in NSCLC is poorly elucidated. Here, we used whole transcriptome sequencing to systematically investigate the RNAs-associated regulatory network in the PD treating NSCLC cell lines. A total of 942 significantly dysregulated RNAs were obtained. Among those, five circRNAs and six IncRNAs were rigorously selected via database and in vitro validation. In addition, the functional enrichment study of differentially expressed mRNAs, single nucleotide polymorphisms (SNPs) within PD-related mRNA structures, and the interaction between PD and mRNA-related proteins were analyzed through gene set enrichment analysis (GSEA), structural variant analysis, and molecular docking, respectively. With further in vitro validation, the results show that PD inhibits cell proliferation, arrests the cell cycle, and induces cell apoptosis through targeting BCL2-related proteins. We hope these data can provide a full concept of PD-related molecular changes, leading to a new treatment for NSCLC. Full article

An inflammatory myofibroblastic tumor (IMT) is a neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by inflammatory cells, including lymphocytes and eosinophils. It is an ultra-rare tumor, the optimal management of which remains to be defined. Surgery is the treatment of choice for localized tumors. The treatment of advanced disease is not precisely defined. Chemotherapy regimens result in an overall response rate of approximately 50% based on retrospective data. The latest pathophysiological data highlight the role played by tyrosine kinase fusion genes in IMT proliferation. Anaplast lymphoma kinase (ALK) oncogenic activation mechanisms have been characterized in approximately 80% of IMTs. In this context, data regarding targeted therapies are most important. The aims of this article are to review the latest published data on the use of systematic therapy, particularly the use of molecular targeted therapy, and to publish an additional case of an IMT with Ran-binding protein 2 (RANPB2)-ALK fusion showing a long response to a tyrosine kinase inhibitor. Full article

The lack of new drugs and resistance to existing drugs are serious problems in gastric cancer(GC) treatment. The research found polyphenols possess anti-Helicobacter pylori(Hp) and antitumor activities and may be used in the research and development of drugs for cancer prevention and treatment. However, polyphenols are affected by their chemical structures and physical properties, which leads to relatively low bioavailability and bioactivity in vivo. The intestinal flora can improve the absorption, utilization, and biological activity of polyphenols, whereas polyphenol compounds can increase the richness of the intestinal flora, reduce the activity of carcinogenic bacteria, stabilize the proportion of core flora, and maintain homeostasis of the intestinal microenvironment. Our review summarizes the gastrointestinal flora-mediated mechanisms of polyphenol against GC. Full article

Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes. In this study, we clarify the functional role it plays in the morphological characteristics of intracellular vesicle formation as well as apoptosis in A549 human lung cancer cells. CBD treatment shows growth inhibition at concentrations above 20 μM, but FACS analysis shows low efficacy in terms of cell death. Microscopic observations suggest that multiple vesicles were detected in the cytoplasmic region of CBD-treated A549 cells. CBD treatment upregulates apoptosis-related proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin, indicating that CBD regulates several types of cell death. CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components. Treatment combining CBD with GW9662, a PPARγ inhibitor, reduced CBD-induced cytoplasmic vesicle formation. This indicates that PPARγ regulates the vesicle-formation mechanism. However, CBD-treated E-cad KO clones did not show this regulatory mechanism. These results elucidate the pharmacological and molecular networks associated with CBD in PPARγ-dependent vesicle formation and the induction of apoptosis. Full article

Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a systematic study with five different epigenetic enzyme inhibitors (1, UVI5008, MS275, psammaplin A, and BIX01294) targeting either Histone Deacetylase (HDAC) 1 or 1/4, DNA methyltransferase 3a (DNMT3a), Euchromatic histone lysine methyltransferase 2 (EHMT2), or Sirtuin 1 (SIRT1), as well as one drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with gemcitabine was tested and the most efficient combinations were characterized by RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/SIRT1/DNMT3a (UVI5008) or EHMT2 (BIX01294) induced a significant reduction on the cell viability, even in gemcitabine-resistance cells. The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose. Full article

In recent years, the thienopyrazole moiety has emerged as a pharmacologically active scaffold with antitumoral and kinase inhibitory activity. In this study, high-throughput screening of 2000 small molecules obtained from the ChemBridge DIVERset library revealed a unique thieno[2,3-c]pyrazole derivative (Tpz-1) with potent and selective cytotoxic effects on cancer cells. Compound Tpz-1 consistently induced cell death at low micromolar concentrations (0.19 μM to 2.99 μM) against a panel of 17 human cancer cell lines after 24 h, 48 h, or 72 h of exposure. Furthermore, an in vitro investigation of Tpz-1’s mechanism of action revealed that Tpz-1 interfered with cell cycle progression, reduced phosphorylation of p38, CREB, Akt, and STAT3 kinases, induced hyperphosphorylation of Fgr, Hck, and ERK 1/2 kinases, and disrupted microtubules and mitotic spindle formation. These findings support the continued exploration of Tpz-1 and other thieno[2,3-c]pyrazole-based compounds as potential small-molecule anticancer agents. Full article