Search Results (170)

Plant-derived bioactive compounds represent a major foundation of modern anticancer therapy and remain a prolific source of molecules with clinically relevant activity. This review provides an integrated classification of plant-derived anticancer compounds based on their clinical development status and predominant molecular mechanisms of action. Established chemotherapeutic agents, including taxanes, vinca alkaloids, and camptothecin derivatives, are distinguished from investigational phytochemicals such as polyphenols, flavonoids, terpenoids, and alkaloids that are under preclinical or clinical evaluation. These compounds target key hallmarks of cancer through modulation of microtubule dynamics, inhibition of topoisomerases, regulation of oncogenic signaling and epigenetic processes, and suppression of angiogenesis, invasion, and metastasis. Particular emphasis is placed on multitarget phytochemicals that interfere with PI3K/Akt, NF-κB, JAK/STAT, and MAPK pathways, induce apoptosis, and promote epigenetic reprogramming. In addition, major translational challenges, especially limited bioavailability, are discussed alongside advances in nano-enabled delivery systems designed to enhance therapeutic efficacy and reduce systemic toxicity. Collectively, this framework highlights the continuing relevance of plant-derived compounds in oncology and supports their rational integration into precision cancer therapy. Full article

Background: Colchicine is a microtubule-targeting anti-inflammatory agent with emerging relevance in cardiovascular disease; however, its effects on injury-induced vascular remodeling remain incompletely defined. Methods: In this study, a rat iliac artery clamp injury model was used to evaluate the effects of colchicine (0.5 mg/kg/day, oral gavage) over 28 days. Histomorphometric, histopathological, and immunohistochemical analyses were performed to assess vascular remodeling. In parallel, molecular docking and STRING/Cytoscape-based protein–protein interaction (PPI) network analyses were conducted to provide structural and systems-level context. Results: Colchicine significantly reduced intimal thickness, the intima-to-media (I/M) ratio, luminal stenosis, adventitial thickness, and collagen deposition, while preserving the lumen area and improving the remodeling index. Medial thickness was not significantly affected. Proliferative activity showed a decreasing trend without statistical significance. Circulating inflammatory cytokines, including TNF-α and IL-1β, did not differ significantly between groups. Docking analyses suggested potential interactions with β-tubulin, ADAM17, NLRP3, IKKβ, and RELA, while network analysis identified an interaction architecture centered on NF-κB-related regulatory components and inflammasome-associated signaling pathways. Conclusions: Colchicine attenuates injury-induced vascular remodeling in this experimental model. These findings, together with complementary in silico analyses, suggest a multi-target, inflammation-associated framework involving NF-κB-related and inflammasome-linked pathways. The in silico analyses provide supportive mechanistic context but do not establish causal relationships. Full article

Antibody–drug conjugates (ADCs) have become an important class of targeted anticancer therapeutics by integrating the tumor selectivity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads through rational linker design. This review summarizes the structural fundamentals of ADCs, including antibodies, linkers, and payloads, and describes their coordinated mechanism of action. We trace the evolutionary trajectory of ADCs across three generations, highlighting key breakthroughs, limitations, and representative agents for each era. Furthermore, we elaborate on cleavage mechanisms of linkers (cleavable and non-cleavable). We also categorize and discuss cytotoxic payloads, covering traditional microtubule-disrupting agents, DNA-damaging agents, and novel mechanism-based payloads, along with their modification strategies and preclinical/clinical performance. Finally, we discuss representative and clinically influential ADC designs, with emphasis on the relationships among antibody, linker, and payload. Full article

Background: Tubulin plays a pivotal role in cell division and other essential cellular processes, making it a key pharmacological target for cancer therapy, antiparasitic treatments, and neurodegenerative diseases. Numerous compounds have been developed to regulate microtubule polymerization through tubulin binding; however, most have shown significant limitations, including adverse side effects, poor bioavailability and limited specificity. In recent years, peptide-based therapies have gained considerable attention, particularly for their ability to modulate protein–protein interaction while offering improved selectivity and safety profiles. Methods: In this study, we employed an integrated computational–experimental approach combining molecular docking, molecular dynamics simulations, and MM-GBSA free energy calculations to design and evaluate 14 peptides derived from the αβ-tubulin dimer interface. Results: The peptide NH₂-P14-COOH emerged as the most promising candidate, displaying the stronger inhibition of tubulin polymerization activity (IC₅₀ = 11.24 ± 3.82 μM), selective cytotoxicity against NCI-H1299 lung carcinoma cells (IC₅₀ = 45.64 ± 3.20 μM), and no significant toxicity toward non-cancerous EA.hy926 endothelial cells (IC₅₀ > 100 μM). Flow cytometry analysis confirmed that NH₂-P14-COOH induces apoptosis, supporting a mechanism of action based on microtubule disruption. Conclusions: These findings highlight NH₂-P14-COOH as a selective antimitotic peptide with a favorable therapeutic index and demonstrate the potential of structure-guided peptide design for the development of novel microtubule-targeting agents with reduced off-target toxicity. Full article

Ovarian cancer, the most lethal type of tumour of the female reproductive system, severely threatens women’s life and health. Despite paclitaxel being a key chemotherapeutic agent in the standard treatment for ovarian cancer, the majority of patients eventually develop resistance to paclitaxel, constituting a significant obstacle to successful treatment. KIF26B, a kinesin family protein, is involved in various cancers, but its role in ovarian cancer and chemotherapy resistance is unclear. In this study, we evaluated the role of KIF26B in drug-resistant ovarian cancer and the underlying mechanisms. Bioinformatics analysis revealed that KIF26B was highly expressed in ovarian cancer tissues and was associated with poor clinical characteristics. Moreover, KIF26B expression was consistently high in chemotherapy-resistant tissues across multiple treatment subgroups, with ROC curve analyses confirming its predictive power for chemoresistance, particularly in advanced serous ovarian cancer. To further investigate the role of KIF26B in ovarian cancer resistance, the effects of KIF26B on cell proliferation, colony formation, the cell cycle, apoptosis, and microtubule polymerization under paclitaxel treatment were assessed. KIF26B knockdown significantly reduced paclitaxel resistance in ovarian cancer cells, inhibited cell proliferation, and promoted apoptosis. Furthermore, KIF26B interference induced cell cycle arrest and altered microtubule polymerization dynamics in paclitaxel-resistant cells. Additionally, our analyses revealed a negative correlation between KIF26B and SLC7A11 in ovarian cancer, particularly in chemoresistant tissues. Combined KIF26B and SLC7A11 expression provided stronger prognostic value than either gene alone did, and functional assays demonstrated that SLC7A11 contributed to the regulation of the KIF26B-mediated paclitaxel response. Overall, our results indicate that KIF26B is crucial for ovarian cancer progression and chemotherapy resistance, likely through SLC7A11 regulation. KIF26B may serve as a potential therapeutic target for overcoming paclitaxel resistance. Full article

Despite significant advances in oncology, current cancer therapies remain constrained by toxicity, resistance, and limited selectivity. Endophytic fungi symbiotic microorganisms inhabiting plant tissues represent a sustainable and underexplored source of structurally diverse anticancer metabolites. These include alkaloids, terpenoids, polyketides, and peptides that disrupt microtubule dynamics, interfere with DNA replication, and induce mitochondrial-mediated apoptosis. They also modulate key oncogenic signalling pathways such as nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), thereby enhancing the efficacy of existing chemotherapies. Endophyte derived compounds further inhibit angiogenesis, suppress metastasis, and stimulate immune responses, offering multi-target mechanisms with reduced toxicity. This review examines strategies that enhance the discovery and yield of these bioactive metabolites, including One Strain Many Compounds (OSMAC), microbial co-culture, epigenetic activation, genome mining, and synthetic biology. A comparative assessment of endophyte-derived versus conventional anticancer agents highlights their potential for scalable, eco-sustainable production. Collectively, endophytic fungi are positioned as promising contributors to the next generation of accessible, cost-effective, and environmentally responsible anticancer therapies. Full article

Background: Resistance to HER2-targeted therapies remains a major limitation in the treatment of HER2-positive breast cancer, where disease progression inevitably occurs in advanced stages. Development of next-generation strategies that retain activity in resistant disease is therefore a critical priority. Disitamab vedotin (RC48) is a novel antibody–drug conjugate (ADC) targeting HER2 that couples a humanized anti-HER2 antibody to the potent microtubule-disrupting agent monomethyl auristatin E. Methods: We compared the activity and mechanism of action of RC48 with that of trastuzumab emtansine (T-DM1) across HER2-positive and HER2-low cellular models, including multiple sublines resistant to current HER2-targeted agents. Results: In HER2-overexpressing breast cancer cell lines, RC48 consistently demonstrated superior antiproliferative effect with respect to T-DM1. Treatment with RC48 induced G2/M arrest and apoptotic cell death, associated with increased pHistone-H3 and cyclin B1 and downregulation of Wee1, consistent with blockade of cell cycle progression in mitosis. Although RC48 and T-DM1 internalized similarly, RC48 displayed more efficient intracellular payload release, providing a mechanistic explanation for its enhanced efficacy. Notably, RC48 retained strong activity in BT474-derived sublines resistant to T-DM1, lapatinib, or neratinib, inducing cell cycle arrest, apoptosis, and caspase activation in all resistant models. In contrast, T-DM1 exhibited only partial effects in resistant cells and was completely ineffective in a T-DM1-refractory clone. Conclusions: Together, these findings identify disitamab vedotin as a potent next-generation HER2-targeting ADC with the unique capacity to overcome acquired resistance to HER2-directed therapies. RC48 represents a promising therapeutic strategy for patients with refractory HER2-positive breast cancer and warrants further clinical investigation. Full article

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates a broad spectrum of genes with oncogenic potential, thereby serving as a critical driver of tumorigenesis. Canonical STAT3 function is mediated through tyrosine phosphorylation, which enables dimerization and transcriptional activation, whereas serine phosphorylation of STAT3 has a postulated role in fine-tuning canonical functions and contributes to non-canonical roles as well. One of the transcriptional targets of STAT3 is the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein, itself subject to phosphorylation-dependent regulation. In this study, we investigated the effect of chelidonine, an alkaloid component of Chelidonium majus L., on STAT3/Bcl-2 signaling in human T leukemia/lymphoma cells, reported to have numerous effects in common with microtubule-targeting agents (MTAs). Flow cytometry and confocal microscopy revealed that chelidonine transiently increased both serine-phosphorylated STAT3 (pSer-STAT3) and Bcl-2 levels in a distinct subpopulation of cells, with near-complete overlap between the affected cells. This effect appeared at least partially independent of interleukin-2 (IL-2) and was associated with the M-phase of the cell cycle, as indicated by enhanced phosphorylation of Bcl-2 at serine 70 and nuclear morphology characteristic of mitosis. Our study provides the first single-cell evidence that STAT3 and Bcl-2 undergo concurrent serine phosphorylation as a response to chelidonine treatment, with the effect tightly linked to the M-phase. Full article

Chalcones have garnered significant research interest due to their various medical bioactivities. Several chalcone compounds have been approved for marketing and clinical use in the treatment of various diseases. A critical aspect of the action of chalcones is their effect on microtubules. They are considered an excellent target for chemotherapeutic agents for the treatment of cancer. Consequently, scientists are constantly developing novel chalcone drug agents and also innovative drug delivery strategies. In this manuscript, we report the first synthesis of 12 new visible-light-activated, photoswitchable chalcone-based microtubule inhibitors (17a–17l). Among the obtained compounds, one photoswitch demonstrated light-dependent cytotoxicity in the PC-3 cancer cell line. The IC₅₀ value of the Z conformer was determined to be 4.75 ± 1.00 μM after 48 h of treatment. The E conformer exhibited slightly lower activity compared to the Z conformer, with an IC₅₀ value of 5.80 ± 0.80 µM following 48 h of incubation. In this study, NMR and UV spectroscopy, along with computational methods, were employed. Full article

Background/Objectives: Cancer persists as a leading concern in the current medical field, and current therapies are limited by toxicity, cost, and resistance. Targeted inhibition of tubulin polymerization is considered as a promising therapeutic strategy for cancer treatment. Methods: Thirty-one new tubulin polymerization inhibitors were designed via molecular hybridization techniques, and BLI technology was employed to quantitatively investigate their interactions with tubulin. Antiproliferative activities against MCF-7, MDA-MB-231, A549, and HeLa cell lines was evaluated using the CCK8 assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. The anti-tumor activity of compound B6 was validated in a mouse melanoma tumor model. Results: Compounds exhibited varying degrees of antiproliferative activity against four tumor cell lines. Among them, compound B6 was the most promising candidate and displayed strong broad-spectrum anticancer activity with an average IC₅₀ value of 2 μM. The mechanism studies revealed that compound B6 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, and arrested the cell cycle at G2/M phase. Furthermore, B6 displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 70.21% (50 mg/kg). Conclusions: This work shows that B6 is a promising lead compound deserving further investigation as a potential anticancer agent. Full article

Background: Hypoxia-inducible factor-1α (HIF-1α) is a well-known transcriptional regulator that mediates a broad spectrum of cellular responses to hypoxia, including angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. These activities can be achieved by upregulation of numerous genes, such as vascular endothelial growth factors, fibroblast growth factors, and platelet-derived growth factors, which are involved in the growth regulation of normal tissues and solid tumors. Notably, HIF-1α-mediated regulation of the solid tumor’s microenvironment effectively modulates tumor sensitivity to anticancer therapies and thereby can contribute to disease progression. Methods: The study was performed on breast, lung and prostate cancer cell lines. Protein expression was examined by western blotting. Antitumor activity of 2-ANPC was measured by syngeneic 4T1 breast cancer mouse model. Results: We show here that a 2-aminopyrrole derivative (2-amino-1-benzamido-5-(2-(naphthalene-2-yl)-2-oxoethylidene)-4-oxo-4,5-dihydro-1-H-pyrrole-3-carboxamide—2-ANPC), previously shown as a potent microtubule-targeting agent, effectively downregulates HIF-1α expression in a broad spectrum of cancer cell lines, including breast, lung, and prostate cancer. The downregulation of HIF-1α expression in 2-ANPC-treated cancer cells was due to enhanced proteasome-mediated degradation, whereas the proteasome inhibitor MG-132 effectively reversed this downregulation. 2-ANPC’s potency in downregulating HIF-1α was also shown in vivo by using the 4T1 breast cancer syngraft model. Importantly, this 2-aminopyrrole derivative also downregulated the expression of vascular endothelial growth factor receptors 1 and 3 (VEGFR1 and 3) in 4T1 tumors, which correlated with decreased tumor weight and size. As expected, an increase in apoptotic (i.e., cleaved caspase-3-positive) cells was detected in 4T1 tumors treated with 2-aminopyrrole derivative. Lastly, using various computational tools, we identified four potential binding sites for 2-ANPC to interact with HIF-1α, HIF-1β, and the p300 complex. Conclusions: Collectively, we show here, for the first time, that HIF-1α is a novel molecular target for the 2-aminopyrrole derivative (2-ANPC), thereby illustrating it as a potential scaffold for the development of potent chemotherapeutic agents with anti-angiogenic activity. Full article

Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. Methods: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. Results: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG–HGG and LGG–GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. Conclusions: Glioma grade comparisons reveal a shared neuronal–synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron–glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation. Full article

Background/Objectives: Microtubule-targeting agents remain foundational components of anticancer chemotherapy, yet their clinical utility is constrained by resistance and toxicity. Methods: Here, we present a theoretical exploration of a plausible “dual” binding pocket that spans the α-tubulin pironetin site and the inter-subunit todalam site. Eight virtual chimeric ligands, each merging key pharmacophoric elements of pironetin and todalam, were constructed and covalently docked to Cys316 of α-tubulin. Results: Covalent docking followed by 200 ns all-atom molecular dynamics simulations revealed that two derivatives (compounds 4 and 8) stably occupy the merged cavity, simultaneously anchoring in the pironetin region via Michael addition and in the todalam region via π-stacking and hydrogen bonding. These hybrids preserved the critical hydrogen-bonding networks of both parent ligands and exhibited low ligand RMSD values (~1.5 Å) and compact radii of gyration throughout the simulations, indicating a tight, persistent binding. Estimated HYDE affinities of 1.5 µM for compound 4 and 17.6 µM for compound 8, calculated with SeeSAR, suggest that covalent engagement can compensate for moderate non-covalent binding scores. Conclusions: In summary, our results provide compelling grounds for developing a new class of α-tubulin inhibitors that engage the hybrid pocket, laying a foundation for the structure-guided synthesis of first-in-class dual-site compounds capable of overcoming resistance to conventional microtubule-targeting drugs. Full article

Objective: Identifying biomarkers that predict metastatic potential or guide treatment selection is critical for improving breast cancer (BC) management. Previously, we established the Mitotic Network Activity Index (MNAI) as a prognostic marker in BC. Here, we bioinformatically and experimentally evaluated MNAI as a biomarker for metastasis risk and therapeutic response. Methods: We used Kaplan–Meier and Cox proportional hazard regression analyses to assess the association between MNAI and distant metastasis-free survival (DMFS) across 14 published BC datasets. A total of 16 publicly available clinical trial datasets, including the I-SPY trials, were used to evaluate the predictive value of MNAI for treatment response. Additionally, wound-healing and transmembrane assays were conducted to determine the effects of PLK1, CHEK1, and BUB1 inhibition on BC cell migration and invasion. Results: High MNAI levels were strongly associated with shorter DMFS. Multivariate analysis further confirmed MNAI as an independent risk factor for DMFS, beyond estrogen receptor status and PAM50-based molecular subtypes. Functionally, pharmacologic disruption of the mitotic network using PLK1, CHEK1, or BUB1 inhibitors significantly reduced cell migration and invasion in MDA-MB-231 and BT-549 BC cell lines. Moreover, BC cells with high MNAI increased sensitivity to microtubule-targeting agents such as docetaxel, paclitaxel, and ixabepilone but increased resistance to tamoxifen, AKT1/2 inhibitors, and mTOR inhibitors. Consistent with these findings, analysis of 16 clinical trial cohorts revealed that patients with high MNAI achieved higher pathological complete response rates to taxane-containing and ixabepilone-based therapies. Conclusions: Our findings demonstrate the MNAI as a clinically actionable biomarker that can refine risk stratification and guide the selection of targeted or chemotherapy regimens, advancing precision medicine in BC management. Full article

Background: Glioblastoma (GBM) is an aggressive and treatment-resistant brain tumor with few effective therapies. Tubulin polymers are crucial for maintaining cell–cell signaling, cell proliferation, and cell division. Therefore, tubulin has been targeted by medicinal chemists to develop novel therapeutics to treat cancer. In this regard, we developed novel small-molecule tubulin inhibitors as potential therapeutics to treat GBM. Methods: We synthesized a focused library of pyrimidine-containing dihydroquinoxalinone-based analogs and tested nine compounds for cytotoxicity in GBM cell lines using the Sulforhodamine B (SRB) cell viability assay. We identified compound 8c as the most promising compound and evaluated the in vitro effects of 8c on GBM cell growth using live cell imaging and assessed apoptosis using a cell death ELISA. We then tested its anticancer activity in vivo on GBM xenografts grown in immunocompromised mice. Results: Several compounds demonstrated nanomolar IC₅₀ values in cell viability assays and outperformed temozolomide (TMZ), the current standard treatment for GBM patients. We identified compound 8c, which is a pyrimidine analog with a secondary amine, as the lead candidate for GBM studies in vitro and in vivo. Compound 8c reduced cell viability in a dose-dependent manner and induced complete growth arrest within 48 h at 3–10 nM concentrations in GBM cell lines. ELISA confirmed that compound 8c triggered dose-dependent apoptosis, whereas TMZ failed to induce apoptosis at nM concentrations. In vivo, compound 8c significantly inhibited GBM xenograft growth in immunocompromised mice by 66%. Conclusions: The potent tubulin inhibitor compound 8c has strong anti-GBM activity in vitro and in vivo and merits further preclinical development. Full article