Search Results (732)

Phthalocyanines (Pcs) are well-established photosensitizers in photodynamic therapy, valued for their strong light absorption, high singlet oxygen generation, and photostability. Recent advances have focused on covalently conjugating Pcs, particularly zinc phthalocyanines (ZnPcs), with a wide range of small bioactive molecules to improve selectivity, efficacy, and multifunctionality. These conjugates combine light-activated reactive oxygen species (ROS) production with targeted delivery and controlled release, offering enhanced treatment precision and reduced off-target toxicity. Chemotherapeutic agent conjugates, including those with erlotinib, doxorubicin, tamoxifen, and camptothecin, demonstrate receptor-mediated uptake, pH-responsive release, and synergistic anticancer effects, even overcoming multidrug resistance. Beyond oncology, ZnPc conjugates with antibiotics, anti-inflammatory drugs, antiparasitics, and antidepressants extend photodynamic therapy’s scope to antimicrobial and site-specific therapies. Targeting moieties such as folic acid, biotin, arginylglycylaspartic acid (RGD) and epidermal growth factor (EGF) peptides, carbohydrates, and amino acids have been employed to exploit overexpressed receptors in tumors, enhancing cellular uptake and tumor accumulation. Fluorescent dye and porphyrinoid conjugates further enrich these systems by enabling imaging-guided therapy, efficient energy transfer, and dual-mode activation through pH or enzyme-sensitive linkers. Despite these promising strategies, key challenges remain, including aggregation-induced quenching, poor aqueous solubility, synthetic complexity, and interference with ROS generation. In this review, the examples of Pc-based conjugates were described with particular interest on the synthetic procedures and optical properties of targeted compounds. Full article

Liposomes (LPs) represent one of the most effective nanoscale platforms for drug delivery in cancer therapy due to their favorable pharmacokinetic and various body tissue compatibility profiles. Building on recent findings showing that carbon dots derived from N-hydroxyphthalimide (CDs-NHF) possess intrinsic antitumor activity, herein, we investigate the possibility of preparing complex nano-platforms composed of LPs encapsulating CDs-NHF and/or doxorubicin (DOX) for breast and lung cancer. Various LP formulations were prepared and characterized using Cryo-TEM and Cryo-SEM for morphological analysis, while zeta potential and fluorescence assessments confirmed their stability and optical properties. Cellular effects were evaluated through immunofluorescence microscopy and proliferation assays. LPs-CDs-NHF significantly reduced cancer cell viability at lower concentrations compared to free CDs-NHF, and this effect was further amplified when combined with doxorubicin. Mechanistically, the liposomal formulations downregulated key signaling molecules including pAKT, pmTOR, and pERK, indicating the disruption of cancer-related pathways. These findings suggest that LPs containing CDs-NHF, either alone or in combination with DOX, exhibit synergistic antitumor activity and hold strong promise as multifunctional nanocarriers for future oncological applications. Full article

The incidence and mortality of colorectal cancer (CRC) have increased globally. Several therapeutic approaches have been suggested to address this health issue, in addition to classical methods. Propranolol (PRO) is a beta-blocker that was repurposed to treat infantile hemangiomas, and its anti-tumor activity has been reported. This study aimed to investigate the effects of PRO in a panel of CRC cell lines and its potential impact when combined with chemotherapy. The effects of PRO on cell cytotoxicity, cell morphology, colony formation, cell death induction, cell cycle, mitochondrial and intracellular reactive oxygen species (ROS), and migration were measured in all cells. CompuSyn software was utilized to assess the possible synergistic or additive interaction in the combined treatment. The results showed that PRO suppressed cell proliferation, altered cell morphology, inhibited colony formation, induced apoptosis, altered cell cycle and ROS generation, and inhibited the migration of treated cells in a cell-type-specific, time-dependent, and dose-dependent manner compared with the control. HT-29 was the most sensitive cell line to PRO in terms of cytotoxicity, apoptosis, cell cycle arrest, and ROS generation, while SW-480 was the most sensitive in terms of migration inhibition. Moreover, the PRO and capecitabine combination exhibited a synergistic effect and induced mitochondrial apoptosis in metastatic CRC cells. The data suggest that PRO could be a promising adjuvant therapy for primary and advanced CRC. This study identified variations between CRC cell lines in response to PRO, which may be related to their genetic and epigenetic differences. In addition, the findings highlight the potential of combination strategies to improve therapeutic outcomes in metastatic CRC. Full article

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, their therapeutic potential as monotherapies has been limited by suboptimal efficacy, dose-limiting toxicity, and the emergence of drug resistance. Recent studies have demonstrated that combination therapies involving HSP90 inhibitors and other anticancer agents such as chemotherapeutics, targeted therapies, and immune checkpoint inhibitors can enhance anticancer activity, overcome resistance mechanisms, and modulate the tumor microenvironment. These synergistic effects are mediated by the concurrent degradation of client proteins, the disruption of signaling pathways, and the enhancement of antitumor immunity. However, the successful clinical implementation of such combination strategies requires the careful optimization of dosage, administration schedules, toxicity management, and patient selection based on predictive biomarkers. In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges associated with HSP90 inhibitor-based combination therapies. We also discuss future directions leveraging emerging technologies including multi-omics profiling, artificial intelligence, and nanoparticle-mediated delivery for the development of personalized and effective combination regimens in oncology. Full article

This study aimed to investigate the underlying mechanisms by which dandelion extract inhibits the proliferation of breast cancer MDA-MB-231 cells. Dandelion root and leaf extracts were prepared using a heat reflux method and subjected to solvent gradient extraction to obtain fractions with different polarities. MTT assays revealed that the ethyl acetate fraction exhibited the strongest inhibitory effect on cell proliferation. LC-MS analysis identified 12 potential active compounds, including sesquiterpenes such as Isoalantolactone and Artemisinin, which showed significantly lower toxicity toward normal mammary epithelial MCF-10A cells compared to tumor cells (p < 0.01). Mechanistic studies demonstrated that the extract induced apoptosis in a dose-dependent manner, with an apoptosis rate as high as 85.04%, and significantly arrested the cell cycle at the S and G2/M phases. Label-free quantitative proteomics identified 137 differentially expressed proteins (|FC| > 2, p < 0.05). GO enrichment analysis indicated that these proteins were mainly involved in cell cycle regulation and apoptosis. KEGG pathway analysis revealed that the antitumor effects were primarily mediated through the regulation of PI3K-Akt (hsa04151), JAK-STAT (hsa04630), and PPAR (hsa03320) signaling pathways. Moreover, differential proteins such as PI3K, AKT1S1, SIRT6, JAK1, SCD, STAT3, CASP8, STAT2, STAT6, and PAK1 showed strong correlation with the core components of the EA-2 fraction of dandelion. Molecular docking results demonstrated that these active compounds exhibited strong binding affinities with key target proteins such as PI3K and JAK1 (binding energy < −5.0 kcal/mol). This study elucidates the multi-target, multi-pathway synergistic mechanisms by which dandelion extract inhibits breast cancer, providing a theoretical basis for the development of novel antitumor agents. Full article

Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral drug delivery system, KGM-CUR/PSM microspheres, to achieve precise drug release in CRC and enhance tumor-specific drug accumulation, which leverages high ROS levels in CRC and the β-mannanase overexpression in colorectal tissues. Methods: In this study, we synthesized a ROS-responsive prodrug polymer (PSM) by conjugating polyethylene glycol monomethyl ether (mPEG) and mesalazine (MSL) via a thioether bond. CUR was then encapsulated into PSM using thin-film hydration to form tumor microenvironment-responsive micelles (CUR/PSM). Subsequently, konjac glucomannan (KGM) was employed to fabricate KGM-CUR/PSM microspheres, enabling targeted delivery for colorectal cancer therapy. The ROS/enzyme dual-response properties were confirmed through in vitro drug release studies. Cytotoxicity, cellular uptake, and cell migration were assessed in SW480 cells. In vivo efficacy was evaluated in AOM/DSS-induced CRC mice, monitoring tumor growth, inflammatory markers (TNF-α, IL-1β, IL-6, MPO), and gut microbiota composition. Results: In vitro drug release studies demonstrated that KGM-CUR/PSM microspheres exhibited ROS/enzyme-responsive release profiles. CUR/PSM micelles demonstrated significant anti-CRC efficacy in cytotoxicity assays, cellular uptake studies, and cell migration assays. In AOM/DSS-induced CRC mice, KGM-CUR/PSM microspheres significantly improved survival and inhibited CRC tumor growth, and effectively reduced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and myeloperoxidase (MPO). Histopathological and microbiological analyses revealed near-normal colon architecture and microbial diversity in the KGM-CUR/PSM group, confirming the system’s ability to disrupt the “inflammation-microbiota-tumor” axis. Conclusions: The KGM-CUR/PSM microspheres demonstrated a synergistic enhancement of anti-tumor efficacy by inducing apoptosis, alleviating inflammation, and modulating the intestinal microbiota, which offers a promising stimuli-responsive drug delivery system for future clinical treatment of CRC. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by a dense desmoplastic stroma and a highly immunosuppressive tumor microenvironment (TME). The focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is considered a critical regulator of various cellular processes involved in cancer development. FAK inhibitors (FAKi) have proven to be promising therapeutics for cancer treatment including for pancreatic cancer. As monotherapy, however, FAKi showed only a modest effect in clinical studies. In this study, we investigated the cytotoxicity of six FAKi (Defactinib, CEP-37440, VS-4718, VS-6062, Ifebemtinib and GSK2256098) used in clinical trials on five pancreatic tumor cell lines. We further examined whether their anti-tumor activity can be enhanced by combination with the oncolytic coxsackievirus B3 (CVB3) strain PD-H. IC₅₀ analyses identified Defactinib and CEP-37440 as the most potent inhibitors of tumor cell growth. VS-4718, VS-6062, and Ifebemtinib showed slightly lower activity, while GSK2256098 was largely ineffective. The combination of Defactinib, CEP-37440, VS-4718, and VS-6062 with PD-H resulted in varying effects on cytotoxicity, depending on the cell line and the specific FAKi, ranging from no enhancement to a pronounced increase. Using the Chou–Talalay method, we determined combination indices (CI), revealing synergistic, additive, but also antagonistic interactions between the respective FAKi and PD-H. Considering both oncolytic efficacy and the CI, the greatest enhancement in oncolytic activity was achieved when VS-4718 or CEP-37440 was combined with PD-H. These findings indicate that co-treatment with PD-H can potentiate the therapeutic activity of the selected FAKi and may represent a novel strategy to improve treatment outcomes in PDAC. Full article

Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/Bak^DKO cells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules. Full article

Modern oncology increasingly relies on personalized strategies that aim to customize medical interventions, using both tumor biology and clinical features to enhance efficacy and minimize adverse effects. In recent years, precision medicine has been implemented as part of systemic therapies; however, its integration into radiation therapy (RT) is still a work in progress. Conventional RT treatment plans are based on the Linear Quadratic (LQ) model and utilize standardized alpha and beta ratios (α/β), which ignore the high variability in terms of treatment response between and within patients. Recent advances in radiobiology, as well as general medical technologies, have also driven a shift toward more tailored approaches, including in RT. This review provides an overview of current knowledge and future perspectives for the personalization of RT, highlighting the role of tumor and patient-specific biomarkers, advanced imaging techniques, and novel therapeutic approaches. As an alternative to conventional RT modalities, hadron therapy and Flash RT are discussed as innovative approaches with the potential to improve tumor targeting while sparing normal tissues. Furthermore, the synergistic combination of RT with immunotherapy is discussed as a potential strategy to support antitumor immune responses and overcome resistance. By integrating biological insights, technological innovation, and clinical expertise, personalized radiation therapy may significantly advance the precision oncology paradigm. Full article

Immunotherapy targeting the immune functions of the tumor microenvironment (TME) is beneficial for colorectal cancer; however, the response rate is poor. Ciprofloxacin is a fluoroquinolone-class antibiotic that is used to treat bacterial infections. The purpose of this study is to assess the mechanism of ciprofloxacin that enhances anti-PD1 in colorectal cancer. We found that ciprofloxacin induced cytosolic DNA, including single-stranded and double-stranded DNA, formation in mouse CT26 colorectal adenocarcinoma cells. Molecules in DNA-sensing signaling such as cGAS, STING, and IFNβ mRNA and protein expression were elicited after ciprofloxacin treatment in CT26 cells. STING siRNA abrogated the cGAS-STING pathway activation by ciprofloxacin. In vivo, ciprofloxacin exhibited a synergistic effect with anti-PD1 to suppress tumor growth in a CT26 syngeneic animal model without biological toxicity. The examination of TME revealed that ciprofloxacin, alone and in combination therapy, induced M1 and red pulp macrophage production in the spleen. In tumors, M1 and M2 macrophage levels were increased by ciprofloxacin, and CD8⁺ T cell granzyme B expression was increased after combination therapy. STING showed the highest expression in tumor specimens after combination treatment. Ciprofloxacin may enhance the anti-PD1 efficacy and modulate the TME through the cGAS-STING pathway. Full article

Triple-negative breast cancer (TNBC) frequently evades immune recognition and elimination, resulting in an immunosuppressive microenvironment. The phagocytic activity of tumor-associated macrophages underscores the development of nanomaterials as a promising strategy to target these macrophages and modulate their polarization, thereby advancing immunotherapy against TNBC. This research developed functional polymers that are complexed with therapeutic molecules as a coating strategy for iron oxide nanoparticles. An arginine-based poly (ester urea urethane) polymer complexed with a macrophage-polarizing molecule (APU-R848) could provide a synergistic effect with iron oxide nanoparticles (IONPs) to stimulate the M1-polarization of macrophages at the tumor site, resulting in a versatile nano-platform for immune regulation of TNBC. In the 4T1 in vivo breast tumor model, the APU-R848-IONPs demonstrated an improved intratumoral biodistribution compared to IONPs without a polymer coating. APU-R848-IONPs significantly reversed the immune-suppressive tumor environment by reducing the M2/M1 macrophage phenotype ratio by 51%, associated with an elevated population of cytotoxic T cells and a significantly enhanced production of tumoricidal cytokines. The activated immune response induced by APU-R848-IONP resulted in a significant anti-tumor effect, demonstrating an efficacy that was more than 3.2-fold more efficient compared to the controls. These immune-regulatory pseudo-protein-coated iron oxide nanoparticles represent an effective nano-strategy for macrophages’ regulation and the activation of anti-tumor immunity, providing a new treatment modality for triple-negative breast cancer. Full article

Caffeine, one of the most widely consumed bioactive compounds worldwide, is gaining recognition for its potential anticancer properties beyond its well-known neurological and metabolic effects. Mechanistically, caffeine exerts anti-tumor activity by modulating key cellular pathways involved in carcinogenesis, including the inhibition of phosphodiesterases, antagonism of adenosine A2A receptors, and disruption of the DNA damage response through ATR-Chk1 pathway inhibition. These actions collectively promote apoptosis, suppress tumor cell proliferation, and impair metastatic spread. In vitro and in vivo studies have demonstrated that caffeine can enhance the cytotoxic effects of chemotherapeutic agents and radiation therapy, suggesting a synergistic role in conventional cancer treatments. Epidemiological data further supports an inverse association between habitual caffeine consumption and the incidence of several cancers, notably liver, colorectal, breast, and prostate cancers. Among these, the most consistent experimental and clinical evidence exists for liver and colorectal cancer, where caffeine’s modulatory effects on inflammation and cell proliferation have been repeatedly observed. Additionally, caffeine’s anti-oxidant and anti-inflammatory properties may contribute to a microenvironment less conducive to tumor initiation and progression. While promising, the anticancer effects of caffeine are influenced by factors such as dosage, individual genetic variability, and cancer type, underscoring the need for further clinical investigation. This review explores the emerging role of caffeine as a potential chemopreventive and adjuvant therapeutic agent in oncology. Full article

Background/Objectives: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease (IBD) that poses a significant gastroenterological challenge. Methods: This study investigates the protective effects of garlic peel extract (GPE) in a rat model of acetic acid (AA)-induced colitis. Rats received oral GPE (100 mg/kg) for 14 days prior to AA administration, and this continued for 14 days post-induction. Results: GC-MS analysis of GPE identified several key phytochemicals, primarily methyl esters of fatty acids (62.47%), fatty acids (10.36%), fatty acid derivatives (6.75%), and vitamins (4.86%) as the major constituents. Other notable compounds included steroids, natural alcohols, organosulfur compounds, fatty aldehydes, carotenoids, sugars, and glucosinolates. GPE treatment significantly improved body weight and colon length. Biochemical analysis showed that GPE downregulated the levels of the pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, IL-17, tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB), compared to the colitis (AA) group. Additionally, GPE reduced the oxidative stress (OS) biomarkers, including myeloperoxidase (MPO) and malondialdehyde (MDA), as well as caspase-3, a marker for apoptosis. Furthermore, GPE treatment resulted in enhanced activities of the enzymatic antioxidants catalase (CAT) and superoxide dismutase (SOD), along with increased levels of the anti-inflammatory cytokine IL-10. These findings were supported by histological evidence. Conclusions: Collectively, GPE holds promise as a therapeutic strategy for UC, owing to its natural bioactive compounds and their potential synergistic anti-inflammatory, antioxidant, and anti-apoptotic effects. Full article

Triple-negative breast cancer (TNBC) poses significant challenges due to its high aggressiveness, poor prognosis, and the lack of effective targeted therapies. Paclitaxel (PTX) is a chemotherapeutic agent commonly used in the treatment of TNBC; however, its efficacy is often compromised by drug resistance mediated by autophagy. This study investigated the synergistic effects of the autophagy inhibitor 3-methyladenine (3-MA) and PTX in a TNBC nude mouse model. Monitoring tumor volume and employing HE staining, immunofluorescence, and transmission electron microscopy revealed that PTX monotherapy induced tumor autophagy, characterized by the accumulation of LC3B/VPS34 proteins and an increase in autophagosomes. However, the co-administration of 3-MA reversed this process, significantly decreasing the tumor growth rate. Immunofluorescence and qPCR demonstrated that the combination group had fewer Ki-67-positive cells and more Caspase-3-positive cells, along with upregulated expression of autophagy-related genes and Caspase-family apoptosis genes. Consequently, this study suggests that inhibiting autophagy with 3-MA disrupts the autophagy-mediated protective mechanism of tumor cells, promoting the activation of apoptotic signals and enhancing the antitumor activity of PTX. These findings may offer new molecular mechanistic insights and potential therapeutic strategies for overcoming PTX resistance in TNBC. Full article

Plant-derived polyphenols have become a subject of scientific interest in recent decades due to their widespread occurrence in dietary sources and multi-faceted biological activity, with many of these compounds being recognized as antioxidants and anti-inflammatory agents. Several of these chemicals have, moreover, attracted further interest as their anti-tumoral capabilities were discovered, promising potential implementation in the treatment of proliferative diseases, including various cancers. Malignancies of the central nervous system, the most prevalent of which are glioblastomas, are noted for their aggressiveness, dismal prognosis and low survival rates. This review focuses on two polyphenols with the most expansive body of research on this topic, namely resveratrol and curcumin. It covers recent developments in the research, including in vitro findings, animal model studies and clinical trials on these compounds’ effects on the growth and progression of glial tumors of the central nervous system. Its aim is to present the latest findings on the subject of the mechanisms of action of these phytochemicals and their synergistic activity with conventional therapies, as well as strategies to improve their efficacy for future therapeutic applications. Full article