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Background: Cancer remains a major global health challenge, with treatment efficacy often limited by drug resistance and adverse effects. Drug repurposing offers promising opportunities for developing novel anticancer strategies. This study evaluated the cytotoxic, antiproliferative, and pro-apoptotic effects of metformin and caffeine, administered individually and in combination, in human cancer cell lines, as well as their potential interaction mechanisms. Methods: Human cervical carcinoma (HeLa), lung adenocarcinoma (A549), and colorectal carcinoma (HT29) cell lines were treated with metformin (0.05–50 mM) and caffeine (0.5–5 mM), either alone or in combination, for 24 and 48 h. Cell viability and proliferation were assessed using Trypan Blue and sulforhodamine B (SRB) assays. Apoptosis was analyzed by Annexin V/propidium iodide flow cytometry, and p53 expression in HeLa cells was determined by ELISA. Statistical analysis was performed using a one-way ANOVA followed by Tukey’s post hoc test. Results: Metformin induced dose- and time-dependent cytotoxicity in all tested cell lines, with the lowest IC₅₀ values observed in HeLa and A549 cells after 48 h (2.28 and 3.30 mM, respectively; p < 0.05). Caffeine showed moderate antiproliferative activity, with the strongest effects observed at 2.03 mM in HeLa cells and 2.01 mM in HT29 cells (p < 0.05). The combined treatment produced effects that varied depending on both the cell line and exposure time. At earlier time points, transient synergistic effects were observed in certain cell lines, particularly HeLa cells; however, these effects were not sustained over time. With prolonged exposure, the interaction shifted predominantly toward antagonistic effects, indicating the reduced overall efficacy of the combination compared with the expected additive outcomes. Increased apoptosis and elevated p53 expression further supported the activation of tumor-suppressive pathways. Conclusions: Metformin exhibited significant anticancer activity in vitro, supporting its potential repurposing in oncology. However, the addition of caffeine did not uniformly enhance its efficacy and appeared to exert context-dependent effects. Further in vivo studies are required to confirm the clinical relevance of these findings. Full article

The shortage of effective chemotherapeutic agents poses a significant challenge to the global public health system. Cancer is among the leading diseases affecting the human population worldwide. Issues such as drug resistance, toxicity, lack of specificity, poor bioavailability and water solubility, and severe side effects reduce the effectiveness of many existing anticancer drugs. As a result, there is growing interest in discovering a new generation of therapeutic agents to overcome these limitations. Phenolic acids, including ferulic and caffeic acids, are cinnamic acid derivatives with numerous biological effects, including anti-inflammatory, antibacterial, antifungal, antioxidant, antiviral, cytotoxic, and antiproliferative effects. In recent years, drug repurposing and hybridization strategies have emerged as attractive approaches in medicinal chemistry because they may reduce both the cost and time associated with conventional drug discovery. As a result, several researchers have combined ferulic acid and caffeic acid scaffolds with different pharmacophores to generate hybrid compounds with enhanced anticancer potential. This review summarizes recent in vitro and in silico studies published between 2022 and 2025 on ferulic and caffeic acid hybrid compounds that exhibit cytotoxic and antiproliferative effects. Furthermore, the review discusses structure–activity relationship trends, synthetic approaches, and structural modifications associated with improved biological activity. Collectively, the findings highlight the significant potential of ferulic acid and caffeic acid scaffolds in the development of multifunctional anticancer agents. Full article

The worldwide rise in antimicrobial resistance, along with the ongoing prevalence of cancer, underscores the pressing need for novel, safe, and multifunctional therapeutic candidates. Medicinal plants continue to serve as a valuable source of chemically diverse bioactive molecules that modulate multiple biological targets. In this investigation, the preliminary screening of the antibacterial and anticancer activities of an ethanolic extract of Alhagi maurorum (A. maurorum) was comprehensively evaluated using integrated chemical characterization, in vitro bioassays, and in silico approaches. A liquid chromatography–mass spectrometry (LC-MS) analysis demonstrated a rich phytochemical profile including glucosinolates, phenolic acids, gallotannins, fatty acids, alkaloids, carotenoid derivatives, and 2-hexyldecanoic acid-associated constituents. Antibacterial efficacy was assessed by disk diffusion and minimum inhibitory concentration (MIC) testing against Escherichia coli (E. coli ) and Bacillus cereus (B. cereus), with the extract producing inhibition zones similar to those observed with streptomycin. Anticancer effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays with MCF-7 breast carcinoma cells and Hs27 normal fibroblasts over 24, 48, and 72 h., revealing a time-dependent, selective decrease in malignant cell viability with relatively limited toxicity towards normal cells. Induction of apoptosis was further verified by propidium iodide (PI) staining. A molecular docking analysis highlighted 2-hexyldecanoic acid as the principal active compound, with a strong binding affinity for critical bacterial targets (GyrA, GyrB, and RpoB). In silico toxicity and ADME (absorption, distribution, metabolism, and excretion) assessments indicated favorable drug-like properties, good gastrointestinal uptake, and acceptable safety profiles. Altogether, these results provide combined experimental and computational support for A. maurorum as a promising source of dual-purpose antibacterial and anticancer agents and lay a mechanistic foundation for subsequent preclinical studies. Full article

The anti-apoptotic Bcl-2 protein family, frequently upregulated in a wide range of cancers, contributes to tumor persistence and therapeutic resistance, making these proteins attractive targets for structure-based inhibitor development. Betulinic acid-derived hybrids represent promising scaffolds for apoptosis-oriented anticancer drug discovery due to their reported antiproliferative and pro-apoptotic properties. In this study, a virtual library of 152 betulinic acid-derived hybrids was screened against Bcl-2 and Bcl-XL. This molecular docking study using AutoDock Vina identified BA–Celastrol and BA–Proanthocyanidin B2 as top-ranked ligands, with docking scores ranging from −13.00 to −8.7 kcal/mol. Both compounds were further analyzed by 100 ns molecular dynamics simulation runs, which revealed system-dependent ligand behavior rather than uniform preservation of the initial docked pose across all complexes. BA–Celastrol showed a more compact internal ligand conformation in the ligand property and RMSF analyses, whereas BA–Proanthocyanidin B2 showed greater intramolecular flexibility and conformational adaptability. Ligand displacement relative to the protein differed between targets, with BA–Proanthocyanidin B2 showing a more retained profile in the Bcl-XL model and BA–Celastrol showing more moderate positional behavior in the Bcl-2 model. MM-GBSA calculations resulted in free energy values ranging from −4.95 to −31.82 kcal/mol, indicating protein-dependent energetic differences across the investigated systems. Based on docking performance, molecular dynamics stability, and energetic data, both hybrids were ranked as computational candidates for further exploration against Bcl-2 family targets. The present findings, although confined to computational analysis, underscore the need for prioritizing betulinic acid-based hybrids for subsequent experimental evaluation. Full article

Ovarian cancer (OC) remains one of the most lethal gynaecological malignancies, which is mainly due to late diagnosis, high frequency of metastasis, and the risk of developing resistance to systemic therapy. In recent years, exosomes—small extracellular vesicles (EVs) secreted by cancer cells and components of the tumour microenvironment (TME)—have been identified as potential mediators of OC progression. Exosomes participate in intercellular communication and enable the transfer of RNA, proteins, and lipids. These vesicles may modulate the immune response, promote angiogenesis, remodel the extracellular matrix, and drive epithelial–mesenchymal transitions. Exosomes also appear to play a role in the development of drug resistance via direct transfer of resistance factors or indirect modification of TME. In this review article, we summarise current knowledge on the biological role of exosomes in OC pathogenesis. We also discuss their possible diagnostic, prognostic, and therapeutic relevance. The properties and composition of exosomes make them promising noninvasive liquid biomarkers and convenient carriers for anticancer drugs. However, to fully exploit their potential, further large-scale preclinical and clinical studies are required, which should focus primarily on standardising research methods and assessing the safety and efficacy of exosome-based diagnostic and therapeutic methods. Full article

Tumor cell heterogeneity and multicellular interactions critically influence drug resistance, recurrence, and prognosis. Here, CPcellsubpopulation, a computational framework integrating scRNA-seq, bulk RNA-seq, and clinical data was developed to identify cancer progression-associated cell subpopulations. Then, the integrated analyses of scRNA-seq and spatial transcriptomics were performed to predict potential interactions, identify critical transcription factors, and predict candidate anticancer drugs. Across nine cancers, we detected cancer progression-associated cell subpopulations significantly linked to prognosis, with consistent patterns across cancer types. In renal cell carcinoma (RCC), we identified conserved metabolic^high UBE2C+ cancer cells linked to poor outcomes, metabolic reprogramming and low differentiation, and PLK1+ NK cells, plasma cells, and CDC20+ macrophages associated with advanced stages and unfavorable prognosis. Spatial mapping revealed spatial association of RCC progression-associated cancer and immune cell subpopulations, suggesting the potential role of the VEGF, GDF, PTN and IL16 pathways in the remodeling of the tumor microenvironment. Gene regulatory network analysis highlighted RAD21 as a key regulator linking metabolism and therapy resistance. This study provides a systematic pipeline to delineate cancer progression-associated cell subpopulations, uncovers metabolic^high UBE2C+ cancer cells as progression-associated tumor cell population, and nominates critical regulators and compounds as therapeutic targets. Full article

Autophagy and apoptosis are two evolutionarily conserved catabolic processes that play important roles in maintaining cellular homeostasis and in determining cell fate when cells are exposed to various stresses in vivo. The interaction between autophagy and apoptosis has been studied extensively in cancer research, and it has been shown to affect cancer initiation and tumor formation, disease progression, therapeutic resistance, and overall survival. Autophagy typically functions as a cytoprotective mechanism in cancer cells subjected to metabolic, hypoxic, or therapeutic stress, whereas apoptosis primarily functions as an intrinsic programmed cell death pathway. While apoptosis and autophagy function as distinct pathways, there is significant molecular crosstalk, allowing cells to modulate their behavior from survival to death depending on the severity and duration of exposure to a given stressor and the cellular environment. This review examines the molecular landscape of the autophagy–apoptosis interplay in cancers, with special attention paid to the major signaling pathways involved and their biological outcomes in oncology. We examine the molecular mechanisms and signal transduction pathways involved in the crosstalk between autophagy and apoptosis in cancer. In particular, we focus on several key proteins that regulate this crosstalk, including kinases, caspases, heat shock proteins and transcription factors. Furthermore, we describe the major signal transduction pathways that regulate this crosstalk, including the PI3K/Akt/mTOR, MAPK, unfolded protein response, oxidative stress, and calcium signaling pathways. Additionally, we discussed how dysregulation of these pathways contributes to cancer progression and treatment resistance. Finally, we summarized the use of currently available therapeutic agents targeting the crosstalk between autophagy and apoptosis, including FDA-approved drugs and natural products, with the potential to enhance the effectiveness of anticancer treatments. A better understanding of this complex process will allow the development of new, precision-based, combination cancer therapies. Full article

Introduction: Heat shock proteins (HSPs) are stress-responsive molecular chaperones that are frequently dysregulated in cancer and contribute to tumorigenesis, invasion, metastasis, immune interactions, and resistance to therapy. Distinct HSP families, including HSP27, HSP60, HSP70, HSP90, and HSP110, promote malignant progression through complementary effects on apoptosis regulation, mitochondrial function, proteostasis, and stabilization of oncogenic signaling pathways. This makes HSPs attractive therapeutic targets. Their coordinated roles within stress-adaptive chaperone networks further garner interest in targeting multiple HSP families in cancer therapy. Discussion: Preclinical and clinical studies have established multiple HSP families as promising anticancer targets; however, clinical translation of HSP-directed therapies has been challenged by toxicity, compensatory heat shock responses, and resistance mechanisms. Many N-terminal HSP90 inhibitors have shown clinical utility but have also highlighted the need for alternative approaches, including C-terminal inhibition, HSP70-directed therapies, and rational combination strategies targeting compensatory survival pathways. Emerging inhibitors targeting HSP27, HSP60, and HSP110, as well as HSP-based vaccines, further expand therapeutic opportunities across cancer subtypes. Collectively, these approaches highlight the growing therapeutic relevance of disrupting interconnected HSP networks rather than targeting individual chaperones in isolation. Conclusions: Future development of heat shock protein-targeted therapies will require a deeper understanding of HSP-mediated chemoresistance. Clinical trial and drug development approaches may benefit from combination or multi-targeted strategies that simultaneously disrupt multiple components of the heat shock protein network to achieve more durable anticancer responses. Full article

Reactive oxygen species contribute to the cytotoxic effects of anticancer drugs; however, the clinical relevance of systemic antioxidant capacity in metastatic colorectal cancer (CRC) remains unclear. In this original single-center observational cohort study, we examined the association of baseline blood antioxidant capacity with chemotherapy response and prognosis in 84 patients with stage IV CRC who underwent primary tumor resection followed by systemic chemotherapy between 2015 and 2020. Baseline antioxidant capacity was assessed preoperatively using biological antioxidant potential (BAP) assays. Chemotherapy response was evaluated using contrast-enhanced computed tomography at 4 months using Response Evaluation Criteria in Solid Tumors v1.1. Three-year disease-specific survival (DSS) was assessed. Associations with treatment response were analyzed using linear regression. Survival outcomes were evaluated using Kaplan–Meier and Cox proportional hazards models. Baseline BAP was significantly associated with poorer chemotherapy response; higher BAP levels predicted greater treatment resistance in multivariable analysis (p = 0.009). Kaplan–Meier analysis demonstrated significantly worse 3-year DSS in the high-BAP group than in the low-BAP group (35.6% vs. 55.5%, log-rank p = 0.019). In multivariate Cox regression analysis, high BAP independently predicted poor DSS (hazard ratio 2.174, 95% confidence interval 1.103–4.283, p = 0.009). Elevated baseline systemic antioxidant capacity was associated with reduced chemotherapy effectiveness and poorer DSS in patients with stage IV CRC. Full article

Cancers are intricate and multifactorial diseases. Despite progress in medicine, there are still some obstacles in their treatment due to drug resistance, the toxicity of combination therapy and lack of drug selectivity toward cancer cells. The solution to this may be multi-target directed ligands (MTDLs), which have gained more and more popularity over the years. This review presents a comprehensive overview of novel potential multi-targeted derivatives of nitrogen-containing heterocycles, as imidazole, pyrazole, 1,2,3-triazole and 1,2,4-triazole. The review gathers the selected literature from 2006 to 2026. The analysis focuses on the potency of the inhibitory activity of selected molecules against a variety of molecular targets, as well as on their interactions with protein binding sites. Additionally, the structure-activity relationship (SAR) studies within the collected series are included. The discussion may contribute to the development of new multi-target anticancer agents. Full article

Gastric cancer (GC) is one of the most aggressive malignancies with a dismal prognosis, late diagnosis, and limited therapy efficacy. Biologically, GC is associated with multiple barriers to therapeutic response including gastric mucosal layer, acidic tumor microenvironment (TME), high accumulation of extracellular matrix (ECM) components, and limited penetration depth of anticancer drugs into tumor tissue. Furthermore, inherent or acquired drug resistance associated with drug efflux transporters, deregulated autophagy, tumor heterogeneity, and cell survival pathways severely compromise treatment response. Nanotechnology has been widely used to develop next-generation nanotherapeutic delivery systems to overcome these biological barriers. Currently available nanoplatforms such as liposomes, polymeric nanoparticles, dendrimers, and inorganic nanocarriers have improved drug loading capacity, aqueous solubility, circulation time stability, tumor-targeted delivery, and sustained release of chemotherapeutics. Smart and stimuli-responsive nanocarriers can also take advantage of pathological hallmarks of tumors including low pH, redox potential, and overexpressed enzymes for enhanced selective delivery to the tumor site. Nanotherapeutics have also shown promise for co-delivery of multiple therapeutic agents to overcome drug resistance, manipulation of TME, and suppression of autophagy and apoptosis signaling pathways associated with drug resistance. This review discusses recent advances in nanotherapeutics for GC including approaches to overcome biological barriers and drug resistance and highlights translational gaps for clinical development. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, and advanced disease continues to show poor prognosis due to therapeutic limitations and drug resistance. Royal jelly (RJ), a natural functional food and dietary supplement, contains 10-hydroxy-2-decenoic acid (10-HDA), a bioactive fatty acid unique to RJ with demonstrated anticancer potential. This study evaluated the anti-CRC effects and underlying mechanisms of 10-HDA through cellular, animal, and transcriptomic approaches. 10-HDA markedly suppressed CRC cell viability with IC₅₀ of 2.07 mM and 3.49 mM against HCT 116 and HT-29 cells, respectively, reduced gap closure by 29.30%, elevated intracellular reactive oxygen species (ROS), and attenuated xenograft tumor growth dose-dependently. Preliminary safety evaluation suggested that 10-HDA was well tolerated under the tested conditions, with no significant changes in body weight, serum AST, ALT, or ALP levels, or organ histology. Transcriptomic analysis showed significant enrichment of apoptosis and Wnt/β-catenin pathways. Molecular assessments indicated that 10-HDA was associated with alterations in apoptosis-related features, including increased caspase-3 activity, changes in Bcl-2 family proteins, and elevated ROS levels, as well as with modulation of the Wnt/β-catenin signaling pathway. These changes were consistent with enhanced β-catenin degradation and reduced nuclear translocation. It suggests that Wnt/β-catenin may be involved in the anti-CRC effects of 10-HDA. This study mechanistically clarifies the anti-CRC activity of 10-HDA as a natural food-derived bioactive compound, suggesting its therapeutic potential for Wnt/β-catenin dysregulated CRC. Full article

Dpep is a cell-penetrating peptide that targets transcription factors ATF5, CEBPB and CEBPD to selectively suppress growth and survival of diverse tumor cell types in vitro and in vivo. Due to these actions and its apparent safety, the peptide has potential as a cancer therapeutic. How Dpep might be combined with other anti-cancer agents to achieve synergistic efficacy and to overcome possible peptide resistance has not been assessed in depth. Based on prior work indicating that Dpep promotes apoptotic cancer cell death and up-regulates multiple pro-apoptotic and tumor suppressor genes, we studied combinations of Dpep with ABT-263, a pro-apoptotic BCL2 family inhibitor, and decitabine, a hypomethylating drug. Combining Dpep with each agent alone or together synergistically suppressed the growth of a range of solid and liquid tumor cell types. Moreover, the combinations synergistically inhibited the growth of cells lines that were selected either in vivo or in vitro for Dpep resistance. Finally, we tested the combination of Dpep with ABT-263 in a mouse melanoma xenograft model. The combination more effectively inhibited tumor growth than either agent alone and, in contrast to vehicle or ABT-263, produced a 40% durable survival rate. Taken together, these observations highlight potential drug partners for the therapeutic development of Dpep. Full article

The design of multitargeted drug candidates has recently emerged as a highly attractive area of research. Numerous heterometallic compounds have been developed to enhance both the biological efficacy and physicochemical properties of monometallic metallodrugs. Combining classical transition metals with established antitumor activity, such as Pt, Ru, and Au, with other metal-based fragments offers the potential to generate complex compounds with improved pharmacokinetic and pharmacodynamic profiles. Incorporating different bioactive metal cations within a single molecular framework may enhance anticancer activity through metal-specific interactions with distinct biological targets or through improved physicochemical characteristics of the resulting heteronuclear complexes. Recent studies have underscored the significant progress and promising impact of this multitargeted strategy, particularly in systems that combine ruthenium with other biologically active metal centers. This approach may enable selective biological targeting and help overcome drug resistance. This review compiles and analyzes reported ruthenium-based heteronuclear complexes, offering a comprehensive and critical assessment of recent advances in the rational design and synthesis of novel multinuclear compounds as potential chemotherapeutic agents. Particular emphasis is placed on understanding structure–activity relationships, mechanistic pathways, and the role of metal–metal and metal–ligand interactions in modulating biological responses. The findings summarized herein highlight the remarkable efficacy of a wide range of multinuclear ruthenium anticancer complexes and support the hypothesis that synergistic and/or cooperative interactions between distinct metal-based fragments can significantly enhance pharmacological performance, including improved selectivity, stability, and cellular uptake. Furthermore, emerging insights into their modes of action, resistance profiles, and potential for targeted delivery underscore their promise as viable alternatives to conventional therapies. Overall, this dynamic and rapidly evolving field is poised to inspire continued interdisciplinary research and drive the development of next-generation metallodrugs with improved therapeutic indices and clinical potential. Full article

New anticancer therapeutic strategies, including targeting of iron dysregulation in affected cancer types and stages, are urgently needed to decrease the associated annual cancer death rate of about 10 million worldwide. Many tumours evade treatment and support metastatic potential by effluxing iron and upregulating antioxidant systems, leading to suppression of lipid peroxidation and ferroptotic cell death. Similarly, many tumours manipulate the tumour microenvironment (TME) by ensuring the continuous supply of iron. This involves phenotypic modulation of immune cells, including macrophages, neutrophils, regulatory T lymphocytes, and natural killer cells, as well as fibroblasts, contributing to immune evasion and tumour growth. In particular, tumour-associated macrophages (TAMs), which may account for about half of the tumour’s bulk, become progressively heavily loaded with iron and can be detected by magnetic resonance imaging (MRI) technologies. Clinically effective iron chelation therapy protocols in iron-overloaded conditions using the chelating drugs deferoxamine, deferasirox, and especially deferiprone can also potentially remove excess iron from TAMs and may decrease tumour malignancy. Deferiprone can also remove excess iron from iron-loaded renal cancer cells and potentially prevent metastasis in renal carcinoma. The anticancer potential of deferiprone has also been shown in other cancers, including iron removal in prostate cancer and through cancer stem cell inhibition in breast cancer. Many ongoing clinical trials using different drugs and experimental agents for inducing or modulating ferroptosis also support the translational potential of ferroptosis-based therapeutic strategies in selected categories of cancer patients. These advances highlight ferroptosis as a potential key metabolic vulnerability with relevance for treatment-resistant and metastatic tumours. Overall, iron chelation therapeutic approaches and ferroptosis-targeting may be considered for significant use as monotherapies or in combination with other anticancer drugs and could potentially improve therapeutic outcomes and limit disease progression and mortality in many cancers. Full article