Search Results (214)

Background: Colorectal cancer (CRC) is strongly influenced by miRNAs as well as the circadian system. Methods: High-throughput sequencing of miRNAs expressed in the rat colon during 24 h light (L)/dark (D) cycle was performed to identify rhythmically expressed miRNAs. The role of miR-150-5p in CRC progression was analyzed in DLD1 cell line and human CRC tissues. Results: Nearly 10% of mature miRNAs showed a daily rhythm in expression. A peak of miRNAs’ levels was in most cases observed during the first half of the D phase of the LD cycle. The highest amplitude was detected in expression of miR-150-5p and miR-142-3p. In the L phase of the LD cycle, the maximum in miR-30d-5p expression was detected. Gene ontology enrichment analysis revealed that genes interfering with miRNAs with peak expression during the D phase influence apoptosis, angiogenesis, the immune system, and EGF and TGF-beta signaling. Rhythm in miR-150-5p, miR-142-3p, and miR-30d-5p expression was confirmed by real-time PCR. Oncogenes bcl2 and myb and clock gene cry1 were identified as miR-150-5p targets. miR-150-5p administration promoted camptothecin-induced apoptosis. Expression of myb showed a rhythmic profile in DLD1 cells with inverted acrophase with respect to miR-150-5p. miR-150-5p was decreased in cancer compared to adjacent tissue in CRC patients. Decrease in miR-150-5p was age dependent. Older patients with lower expression of miR-150-5p and higher expression of cry1 showed worse survival in comparison with younger patients. Conclusions: miRNA signaling differs between the L and D phases of the LD cycle. miR-150-5p, targeting myb, bcl2, and cry1, can influence CRC progression in a phase-dependent manner. Full article

Aromathecin compounds—which contain the same indolizine core structure as camptothecin-like compounds—are expected to show anticancer activity. Among them, 22-hydroxyacuminatine—which has a substituent on the E-ring of the pentacyclic scaffold—exhibits topoisomerase 1 inhibitory activity; therefore, the development of efficient methods for its synthesis has been actively pursued. Herein, we report a versatile synthetic methodology for introducing various substituents on the E-ring, leading to the total synthesis of 22-hydroxyacuminatine as a model compound of the aromathecin family. The synthesis comprises the following key steps: the synthesis of an isoquinoline N-oxide via the thermal cyclization of 2-alkynylbenzaldehyde oxime, the subsequent Reissert–Henze-type reaction to yield an isoquinolone, and the construction of the indolizine moiety (CD-ring) through C–N bond formation via the Mitsunobu reaction. Consequently, a pentacyclic benz[6,7]indolizino[1,2-b]quinolin-11(13H)-one framework is obtained. Using this methodology, the total synthesis of the natural products norketoyobyrine and naucleficine and an intermediate of the latter, which are indoloquinolizidine-type alkaloids, was achieved, and their antiproliferative activity against HCT-116 human colon cancer cells and HepG2 human liver cancer cells was assessed. Naucleficine and its intermediate exhibited moderate antiproliferative activity against HCT-116 cells, with IC₅₀ values of 55.58 and 41.40 μM, respectively. Full article

Camptotheca acuminata Decne. is an endemic and valuable tree species in China that is renowned for its medicinal and economic value due to secondary metabolites like camptothecin, a potent anti-cancer compound. With wild resources dwindling, it is a key protected species. Predicting and analyzing its suitable habitats under different future environmental scenarios is essential for conservation, introduction, development, and planting strategies. This study used 1008 distribution points and 32 environmental factors, applying the MaxEnt v3.4.4 model and ArcGIS v10.7 software to predict C. acuminata’s potential distribution under four greenhouse gas emission scenarios (RCP2.6, RCP4.5, RCP6.0, and RCP8.5) for the present, 2050, and 2070. This study identifies the key environmental factors influencing its distribution and analyzes habitat trends under various ecological scenarios. The dominant environmental factors are Bio6 (contribution 23%; importance 59.8%), human activity factor (contribution 18.6%; importance 15.7%), Slope2 (contribution 1%; importance 7%), Slope3 (contribution 5.1%; importance 3.4%), elevation (contribution 0.9%; importance 1.7%), and Bio14 (contribution 41.2%; importance 1%). The total potential suitable habitat area for C. acuminata is 1.5796 × 10⁴ km². Except under RCP8.5, where the habitat area continuously increases, the habitat area shows a trend of first increasing and then decreasing. When human activity is considered, the total potential suitable habitat area is 1.8495 × 10⁴ km², with a consistent decrease under all scenarios except RCP8.5. Centroid migration analysis shows that, driven by global warming, the suitable habitats for C. acuminata are shifting toward higher latitudes. This study provides theoretical support for the conservation, resource management, and germplasm protection of C. acuminata under future ecological and environmental changes. Full article

Background/Objectives: Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with significant therapeutic potential, showing emerging applications in drug delivery. This study aimed to develop and evaluate CBG-conjugated nanoparticles (NPs) incorporating tubulin-targeting drugs to enhance anticancer activity. Methods: CBG was conjugated with N-desacetylthiocolchicine, paclitaxel, and camptothecin using sebacic acid and 4,4′-dithiodibutyric acid as linkers, and nanoparticles were obtained. The NPs were characterized by their stability and size (hydrodynamic diameters < 90 nm). Their antiproliferative activity was assessed in three human tumor cell lines and non-tumorigenic cells. Their cellular uptake and mechanisms of action were investigated via confocal microscopy and cell cycle analysis. Results: The chemical composition of the linkers significantly influenced the antiproliferative effect, with the NPs containing 4,4′-dithiodibutyric acid demonstrating higher activity. Notably, NP3b, formulated with this linker, exhibited up to an 80-fold increase in antiproliferative potency compared to its sebacic acid counterpart (NP3a). In mesothelioma cells (MSTO-211H), NP3b displayed significantly higher cytotoxicity than in non-tumorigenic mesothelial cells (MeT-5A), indicating selectivity for cancer cells. Further analysis in glioblastoma cells confirmed that the NPs retained the microtubule-disrupting effects of their parent drugs. Conclusions: These findings highlight the potential of CBG-based NPs as versatile nanomedicine platforms for targeted cancer therapy. This study underscores the importance of linker chemistry in modulating therapeutic efficacy and supports the development of multifunctional drug delivery systems. Full article

This review summarizes the research progress in the co-delivery of natural products (NPs) and small RNAs in cancer therapy. NPs such as paclitaxel, camptothecin, and curcumin possess multi-target antitumor effects, but their applications are limited by drug resistance and non-specific distribution. Small RNAs can achieve precise antitumor effects through gene regulation, yet their delivery efficiency is low, and they are prone to degradation by nucleases. Nanomaterial-based drug delivery systems (nano-DDSs) provide an efficient platform for the co-delivery of both, which can enhance the targeting of their delivery and improve the synergistic antitumor effects simultaneously. The mechanisms of the antitumor action of natural compounds and small RNAs, the design and application of nanocarriers, and the latest research progress in co-delivery systems are introduced in detail in this paper. The application prospects of the co-delivery of natural compounds and small RNAs in cancer therapy are also discussed. Full article

In this study, we constructed a linear antibody–drug conjugate (ADC), 7300-LP1003, by coupling the camptothecin derivative 095 to a linker through an ether bond. In vitro enzyme experiments indicated that LP1003 releases 095 through the action of tissue cathepsin B. Therefore, we introduced lysine pairs with different water-soluble substituents to further modify the linker and synthesized side-chain ADCs 7300-LP3004 and 7300-LP2004, modified by polysarcosine and polyethylene glycol, respectively. In vitro experiments showed that, after incubation at 55 °C in phosphate-buffered saline for 48 h, 7300-LP3004 aggregation was 45.24%, which was significantly lower than that of 7300-LP1003 (77.14%). Cell cytotoxicity assays demonstrated that the side-chain ADCs, 7300-LP3004 and 7300-LP2004, exhibited significantly higher activity (IC50 values of 39.74 nM and 32.17 nM, respectively) compared to the linear ADC and 7300-Deruxtecan (IC50 of 186.5 nM and 124.5 nM, respectively). In the subcutaneous model of SHP-77 NOD scid gamma mice, when the ADC dose was 5 mg/kg, 7300-LP3004 showed the highest tumor inhibition rate with a tumor growth inhibition (TGI) of 106.09%, which was superior to that of the positive control 7300-Deruxtecan, which had a TGI of 103.95%. In conclusion, 7300-LP3004 demonstrated strong antitumor activity and high physicochemical stability, highlighting the need for further research and development of ADC drugs. Full article

Camptothecin and its derivatives (CPTs) are potent antineoplastic agents that exert their effects by inhibiting DNA topoisomerase I, leading to apoptosis during cell proliferation. Since their discovery in the 1960s, CPTs have faced challenges such as low water solubility, pH-dependent lactone ring instability, and severe off-target toxicities. Despite extensive research, only two CPTs, irinotecan and topotecan, have received health authority approval. Ongoing clinical trials continue to explore the use of CPTs in combination with targeted therapies and immunotherapies to expand their clinical use. Drug delivery systems, including liposomes and antibody–drug conjugates (ADCs), have significantly enhanced the therapeutic index of CPTs. Liposomal irinotecan (Onivyde^®, Ipsen, Paris, France) and two ADCs delivering CPT payloads, trastuzumab deruxtecan (Enhertu^®, Daiichi Sankyo, Tokyo, Japan) and sacituzumab govitecan (Trodelvy^®, Gilead Sciences, Inc., Foster City, CA, USA), have demonstrated substantial efficacy and safety. There is promise that novel strategies such as inverse targeting and co-dosing with anti-idiotypic distribution enhancers may expand the utility of CPT ADCs. This review highlights CPT therapies in clinical use and discusses approaches to further enhance their therapeutic selectivity. Full article

As a common malignancy, hepatocellular carcinoma (HCC) proliferation and metastasis could be promoted by ferroptosis and cuproptosis. In this study, we screened out the differentially expressed cuproptosis- and ferroptosis-related genes (CFRGs) and identified the 17 informative prognosis-associated genes. A CFRG scoring model was constructed based on the subtypes identified by consensus clustering analysis and principal component analysis (PCA). Furthermore, the immune profile, expression of immune checkpoint genes (ICGs) and drug susceptibility were also compared between the two CFRG score groups. The results showed that patients with a high CFRG score had higher survival probabilities. The correlation analysis suggested that CFRG scores were negatively correlated with activated CD4.T.cell. The expression patterns of thirty ICGs and the half-maximal inhibitory concentration (IC₅₀) values of 128 drugs displayed significant differences between the two CFRG score groups. A statistically significant difference in the efficacy of sorafenib was found between the two CFRG score groups. Moreover, based on multivariate COX regression analysis and weighted gene co-expression network analysis (WGCNA), we screened DLAT and SLC2A1 as signature genes. Molecular docking analysis revealed that DLAT and SLC2A1 had a strong binding affinity toward camptothecin, rapamycin, dactolisib, and luminespib. The correlation between the CFRG score and single-cell characteristics was further explored. The study depended on our understanding of the biological function of CFRGs in HCC and provided new insights for developing treatment strategies. Full article

Breast cancer is one of the leading causes of cancer-related mortality in women worldwide, highlighting the importance of effective therapies. This study evaluates the interaction between camptothecin, a potent anticancer agent, and two key receptors implicated in breast cancer progression: HER2 (human epidermal growth factor receptor 2) and EGFR (epidermal growth factor receptor), using molecular docking. The results reveal a stronger binding affinity between camptothecin and HER2 than EGFR, in contrast to neratinib, which demonstrated affinity exclusively for HER2. Camptothecin exhibits significant hydrophobic and pi-alkyl interactions with HER2, whereas its interactions with EGFR are primarily mediated by hydrogen bonds. Molecular dynamics (MD) simulations of the camptothecin-HER2 complex indicate stable binding, with minimal fluctuations observed over 100 nanoseconds, confirming the stability of the ligand–receptor interaction. Pharmacokinetic evaluations, based on Lipinski’s rule of five, demonstrate that camptothecin adheres to essential drug-likeness parameters, suggesting favorable bioavailability. Furthermore, the analysis comparing the pharmacological properties of camptothecin with other well-known anticancer compounds, such as neratinib, shows that camptothecin exhibited superior compliance with drug-likeness rules. Despite its low solubility, the binding stability and pharmacokinetic profile suggest its potential as an effective therapeutic agent for breast cancer, particularly when combined with drug delivery systems that enhance solubility. This work underscores the importance of receptor-specific ligand interactions in drug design and highlights the need for further studies into camptothecin’s clinical applications, especially in HER2-positive breast cancer treatment. Full article

Cancer remains a leading cause of death worldwide, highlighting the urgent need for novel and more effective treatments. Natural products, with their structural diversity, represent a valuable source for the discovery of anticancer compounds. In this study, we screened 750 Antarctic extracts to identify potential inhibitors of human topoisomerase 1 (hTOP1), a key enzyme in DNA replication and repair, and a target of cancer therapies. Bioassay-guided fractionation led to the identification of palmitic acid (PA) as the active compound from the Antarctic sponge Artemisina plumosa, selectively inhibiting hTOP1. Our results demonstrate that PA irreversibly blocks hTOP1-mediated DNA relaxation and specifically inhibits the DNA religation step of the enzyme’s catalytic cycle. Unlike other fatty acids, PA exhibited unique specificity, which we confirmed through comparisons with linoleic acid. Molecular dynamics simulations and binding assays further suggest that PA interacts with hTOP1-DNA complexes, enhancing the inhibitory effect in the presence of camptothecin (CPT). These findings identify PA as a hTOP1 inhibitor with potential therapeutic implications, offering a distinct mechanism of action that could complement existing cancer therapies. Full article

Therapeutic challenges persist in the management of non-small cell lung cancer (NSCLC) in oncology. Camptothecins have demonstrated as crucial agents in tumor therapy; however, their efficacy is significantly hindered by adverse effects and drug resistance. Herein, we present a novel camptothecin derivative named 9c, which exhibits impressive anti-NSCLC potency surpassing the widely recognized camptothecin analog FL118 through a novel mechanism. Our findings demonstrated that 9c effectively inhibited tumor malignancy through cell cycle arrest and apoptosis induction with the transcriptional downregulation of anti-apoptotic genes including survivin, Mcl-1, Bcl-2, and XIAP. Mechanistically, 9c induced a wild-type p53 expression by destabilizing the NSA2-EGFR axis, thus delaying the cell cycle progression and ultimately triggering apoptosis. 9c significantly inhibited the growth of the NSCLC xenograft in vivo without observed side toxicity. Importantly, it complemented the therapeutic advantages of the novel drug AMG510 for addressing KRAS-mutant NSCLC. Collectively, these findings position 9c as a promising candidate with innovative approaches to combat NSCLC. Full article

A high-precision biosensor technique is introduced, offering the capability to independently evaluate the effects of anti-cancer drugs on both cancerous (RAJI) and non-cancerous (WIL2S) cells. By analyzing and fitting current change curves and transfer characteristic curves under two drugs, camptothecin and doxorubicin, this technique quantifies both the magnitude of drug-induced current changes in cells and the rate of drug entry into cells. Flow cytometry was utilized to validate the entry rates of two drugs, camptothecin and doxorubicin, into the cells. The biosensor leverages the exceptional sensitivity of two-dimensional electron gas to detect proximal charge variations at ultralow concentrations, even in fluids with high ionic strength. The findings reveal that anti-cancer drugs have a more pronounced impact on tumor cells, with the effects and interaction speeds differing across normal cells and tumor cells. This innovative approach not only enhances our understanding of the specificity and action mechanisms of anti-cancer drugs but also provides a valuable tool for screening potential tumor anti-cancer drugs and advancing targeted cancer therapies. Full article

Senescence is an intricate physiological progression that can be instigated by a multiplicity of factors. Aberrant cellular senescence is capable of precipitating a substantial array of diseases. During chemotherapy, drugs typically tend to gradually accumulate in the liver, thereby inducing liver senescence and leading to a successive deterioration in its physiological function. β-galactosidase (β-gal), serving as a significant index in the exploration of senescence, has attracted considerable attention. In this study, a fluorescence/photoacoustic (FL/PA) biomodal probe (Gal-QCS) was developed based on a hemicyanine fluorophore for the imaging of β-gal in the process of drug-induced liver senescence. Gal-QCS demonstrates rapid responsiveness, high sensitivity, and remarkable selectivity in detecting β-gal in aqueous solutions. After incubation with β-gal, the fluorescence signal at 810 nm significantly increases, and concurrently, the photoacoustic signal at 775 nm also exhibits a substantial increment. Upon the induction of cell senescence with camptothecin, Gal-QCS can expeditiously and selectively image senescent cells. Moreover, after administering this probe to mice with liver senescence, the FL/PA signals in the livers of senescent mice were enhanced by 10.53-fold and 1.43-fold, respectively. This work robustly substantiates the potential and application prospects of Gal-QCS in detecting drug-induced liver senescence, with β-gal serving as a biomarker. Full article

Background: The rapid rise in cancer incidence significantly augments efforts to improve cancer treatments. A multimodal approach in the nanobrachytherapy of solid tumors is one of the promising methods under investigation. This study presents a novel biocompatible lignin-based nanomaterial, loaded with cytostatic agent SN-38 and radionuclide ¹³¹I, for simultaneous radiation and chemotherapy of solid tumors by a nanobrachytherapy approach. Method: Nanoparticles of ~100 nm in size, composed of lignin alone or loaded with 10% (m/m) of SN-38 (SN-38@lignin), were synthesized using a bottom-up approach and characterized. Subsequent radiolabeling of the nanoparticles by ¹³¹I produced ¹³¹I-lignin and ¹³¹I-SN-38@lignin. Their antitumor efficiency was tested against luciferase-expressing 4T1 mouse breast cancer xenografts of ~100 mm³ size on Balb/c mice. Results: An intratumoral injection of 1.85 MBq of ¹³¹I-lignin was retained within the tumor and achieved a moderate twofold decrease in tumor size compared to the control group. Injecting SN-38@lignin containing 25 µg of SN-38 decreased tumor size 3.5-fold. The therapy using the same doses of ¹³¹I-SN-38@lignin produced the most potent antitumor effect, with tumors being 6-fold smaller and having extensive intratumoral necrosis, all of it without signs of systemic toxicity. Conclusions: These results support the intratumoral delivery of lignin-based nanomaterial carrying radioisotopes and camptothecins for effective multimodal anticancer therapy. Full article

Background/Objectives: DNA damage response (DDR) is a highly conserved and complex signal transduction network required for preserving genome integrity. DNA repair pathways downstream of DDR include the tyrosyl-DNA phosphodiesterase1 (TDP1) enzyme that hydrolyses the phosphodiester bond between the tyrosine residue of topoisomerase I (TopI) and 3′-phosphate end of DNA. A small TDP1 subfamily, composed of TDP1α and TDP1β, is present in plants. The aim of this work was to investigate the role of the two TDP1 genes in the DDR context. Methods: A series of Arabidopsis thaliana DDR single and double mutants defective in the sog1, e2fb, pol2A, atm, and atr genes, treated with the genotoxic agents camptothecin (CPT, inhibitor of TopI) and NSC120686 (NSC, inhibitor of TDP1), were used. These compounds were specifically used due to their known impact on the TDP1 function. The effect of the treatments was assessed via phenotypic analyses that included germination percentage, speed, and seedling growth. Subsequently, the expression of the TDP1α and TDP1β genes was monitored through qRT-PCR. Results: Overall, the gathered data indicate that the atm mutant was highly sensitive to NSC120686, both phenotypically and concerning the TDP1α gene expression profiles. Alternatively, the upregulation of TDP1β in e2fb, pol2a, and atr supports its implication in the replication stress response. Conclusions: The current study demonstrates that genotoxic stress induced by CPT and NSC has a genotype-dependent effect reflected by a differential expression of TDP1 genes and early phenotypic development. Full article