Search Results (2,957)

Melanoma is an aggressive malignancy with poor prognosis in advanced stages, and current therapeutic options provide only limited benefits, highlighting the need for novel treatments. Chetomin, a fungal metabolite isolated from Chaetomium cochliodes, has been reported to exhibit diverse biological activities, yet its effects on melanoma cells remain poorly understood. In this study, we evaluated the antitumor potential of chetomin using the human A375 melanoma cell line. Cell viability was assessed with MTT and CellTiter-Glo^® assays, which revealed a significant dose- and time-dependent reduction in proliferation following chetomin exposure. Apoptotic effects were confirmed through Annexin V staining, and immunocytochemical analysis demonstrated a concentration-dependent increase in cleaved PARP1, indicating activation of programmed cell death pathways. Collectively, these findings demonstrate that chetomin effectively inhibits melanoma cell growth and promotes apoptosis. The results suggest that chetomin represents a promising lead compound for melanoma therapy, warranting further investigation into its precise molecular mechanisms. Full article

Background: Most immunologically “cold” tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7/8/9 agonist (CR108) in 4T1 tumors, the underlying mechanism—particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification—remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry/ICS. T-cell receptor β (TCRβ) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies—especially platinum agents—broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-γ⁺ CD8⁺ responses, with platinum agents producing the largest expansions in soluble TAs. TCRβ sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo–TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7/8/9 agonism and support clinical evaluation to convert “cold” tumors into immunologically responsive disease. Full article

Small molecule inhibitors targeting BRAF mutations at V600 and downstream MEK represent a significant advancement in treating BRAF-mutant melanoma. However, resistance mechanisms, often involving reactivation of the MAPK pathway via ERK1/2, limit their efficacy. The ERK1/2 inhibitor ravoxertinib (GDC0994) was tested on melanoma cell lines with and without resistance to BRAFi or BRAFi + MEKi. Short-term assays evaluated cell viability, apoptosis induction, and pathway modulation via Western Blot, while long-term effects were assessed using a colony formation assay. Resistant and parental melanoma cells responded to long-term ERKi treatment with reduced growth, independent of sensitivity to BRAF or MEK inhibitors. Adding ERKi to BRAFi/MEKi significantly enhanced apoptosis and growth inhibition, particularly in resistant lines. Although ravoxertinib alone showed limited antitumor activity, its combination with BRAFi/MEKi yielded substantial benefits, especially in chronic settings. These findings suggest that combinatorial regimens incorporating ERK inhibitors represent a promising therapeutic strategy for BRAF-mutant melanoma. Full article

Colorectal cancer (CRC) remains a leading global health challenge, and natural products are increasingly explored for their multi-targeted therapeutic potential. Litchi chinensis seed extract (LCSE) has shown promising anti-cancer activity in vitro, though its in vivo effects remain underexplored. LCSE was analyzed by colorimetric assays and HPLC to quantify the phytochemical composition. Nude mice bearing HT-29 or SW480 xenografts were orally administered LCSE (0.1 or 0.6 g/kg) daily for 14 days. Tumor volume was measured, and immunohistochemistry was used to assess EGFR, p21, p53, Ki-67, CEA, CK20, CDX2, and Bax expression. Phytochemical profiling demonstrated LCSE contains abundant phenolics and flavonoids, with gallic acid as a predominant constituent, underscoring the potential bioactive properties. LCSE significantly inhibited tumor growth in HT-29 xenografts and dose-dependently reduced EGFR, p21, p53, cell cycle proteins and proliferation/differentiation markers. In SW480 tumors, inhibitory effects were evident primarily at the higher dose, with limited reduction in p53 expression. Bax levels remained unchanged in both models, indicating a non-apoptotic mechanism. No systemic toxicity was observed in treated mice. LCSE exhibits dose-dependent anti-tumor activity in CRC xenografts, likely mediated through suppression of proliferation and modulation of key regulatory proteins rather than apoptosis. These findings support LCSE as a safe, multi-target botanical candidate for CRC intervention and justify further mechanistic and translational studies. Full article

Cancer is a major challenge to global health, and its incidence rate and mortality are expected to continue to rise in the coming decades. Traditional treatment methods such as surgery, radiotherapy, and chemotherapy have limitations, which has prompted people to explore new treatment strategies. As a promising therapeutic approach, oncolytic viruses can selectively target and lyse tumor cells while avoiding damage to normal tissues. This article systematically reviews the mechanisms by which oncolytic viruses induce various forms of cell death, including apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. We explored the direct killing effect of oncolytic viruses and their ability to activate local and systemic antitumor immunity, with a focus on the latest developments in the clinical application of oncolytic viruses, such as the development of novel recombinant viruses. In addition, we also analyzed strategies to enhance the efficacy of oncolytic viruses through gene modification, combination therapy, and targeted delivery systems. A deeper understanding of the multiple mechanisms of action of oncolytic viruses can help us develop more effective and personalized cancer treatment plans. Future research should focus on optimizing oncolytic viruses to overcome tumor drug resistance and improve patient prognosis, making them an important pillar of cancer treatment. Full article

Background/Objectives: The ErbB protein family plays a critical role in the progression of various solid tumors, and HER3 has been implicated in resistance mechanisms to multiple cancer therapies due to its ability to form heterodimers with other ErbB receptors, thereby activating pathways that promote tumor growth and survival. This study aimed to generate and characterize humanized monoclonal antibodies against HER3 to inhibit its function and evaluate their potential as therapeutic agents. Methods: Murine monoclonal antibodies TK-A3 and TK-A4 were humanized and tested for binding to ErbB3 and competition with neuregulin-1β (NRG). Specificity was assessed by ELISA, and epitope identified by X-ray crystallography. Downstream signaling was analyzed by western blot for phosphorylated ErbB3, Akt, and MAPK. Antitumor activity was evaluated in vitro and in a pancreatic cancer xenograft model. A toxicology study was also conducted. Results: TK-hu A3 and TK-hu A4 bound specifically to ErbB3 without cross-reactivity to other ErbB receptors. The ErbB3-TK-hu A3 Fab structure revealed the binding epitope. Both antibodies competed with NRG, inhibiting ErbB3, Akt, and MAPK phosphorylation in a dose-dependent manner. They suppressed cancer cell survival in vitro, and TK-hu A3 significantly delayed tumor growth in vivo. The toxicology study indicated good tolerability. Conclusions: TK-hu A3 emerged as the lead candidate, showing specific HER3 targeting, strong pathway inhibition, and antitumor efficacy in vivo. Beyond standalone use, it could support novel strategies such as T-cell engagers, ADCs, CAR-T, and bispecific antibodies. These findings highlight TK-hu A3 as a promising therapy for HER3-positive, treatment-resistant cancers, meriting further development. Full article

The present study aimed to identify genes encoding enzymes involved in the biotransformation of monoterpenoid (–)-isopulegol by Rhodococcus rhodochrous IEGM 1362. This strain is able to transform (–)-isopulegol with formation of two novel metabolites with promising antitumor and analeptic activities. Cell fractions of rhodococci and specific inhibitor of cytochrome P450-dependent oxygenase activity were used to establish the localization and type of biotransformation enzymes. The expression of nine CYP450 genes selected by bioinformatics analysis was analyzed by quantitative real-time PCR (qRT-PCR). Selection of optimal reference genes for normalization of qRT-PCR results was performed using BestKeeper, Normfinder, geNorm, Delta CT, and RefFinder algorithms. As a result of these studies, the role of CYP450 enzyme complexes in the biotransformation of (–)-isopulegol was confirmed, and their cytoplasmic localization was established. The genes encoding DNA gyrase subunit B (gyrB) and protein translocase subunit A (secA) were selected as the most stable reference genes. The induced expression of the gene encoding CYP450 hydroxylase in the presence of (–)-isopulegol was determined. The obtained data allow us to identify the specific CYP450 enzyme involved in (–)-isopulegol biotransformation by R. rhodochrous IEGM 1362 and lay the foundation for further studies of molecular and genetic mechanisms of monoterpenoid biotransformation. Full article

Immunogenic cell death (ICD) is a specialized form of cell death that triggers antitumor immune responses. In tumors, ICD promotes the release of tumor-associated and tumor-specific antigens, thereby reshaping the immune microenvironment, restoring antitumor immunity, and facilitating tumor eradication. However, the regulatory mechanisms of ICD and its immunological effects vary across tumor types, and a comprehensive understanding remains limited. We systematically analyzed the expression of 34 ICD-related regulatory genes across 33 tumor types. Differential expression at the RNA, copy number variation (CNV), and DNA methylation levels was assessed in relation to clinical features. Associations between patient survival and RNA expression, CNVs, single-nucleotide variations (SNVs), and methylation were evaluated. Patients were stratified into immunological subtypes and further divided into high- and low-risk groups based on optimal prognostic models built using a machine learning framework. We explored the relationships between ICD-related genes and immune cell infiltration, stemness, heterogeneity, immune scores, immune checkpoint and regulatory genes, and subtype-specific expression patterns. Moreover, we examined the influence of immunotherapy and anticancer immune responses, applied three machine learning algorithms to identify prognostic biomarkers, and performed drug prediction and molecular docking analyses to nominate therapeutic targets. ICD-related genes were predominantly overexpressed in ESCA, GBM, KIRC, LGG, PAAD, and STAD. RNA expression of most ICD-related genes was associated with poor prognosis, while DNA methylation of these genes showed significant survival correlations in LGG and UVM. Prognostic models were successfully established for 18 cancer types, revealing intrinsic immune regulatory mechanisms of ICD-related genes. Machine learning identified several key prognostic biomarkers across cancers, among which NT5E emerged as a predictive biomarker in head and neck squamous cell carcinoma (HNSC), mediating tumor–immune interactions through multiple ligand–receptor pairs. This study provides a comprehensive view of ICD-related genes across cancers, identifies NT5E as a potential biomarker in HNSC, and highlights novel targets for predicting immunotherapy response and improving clinical outcomes in cancer patients. Full article

The rising incidence of cancer and the limitations of current therapeutic strategies underscore the urgent need to identify novel bioactive compounds for antitumor drug development. Cyanobacteria are widespread Gram-negative, photoautotrophic prokaryotes that have been recognized as an important source of biologically active secondary metabolites with vast potential for application in the fields of pharmaceutics. The aim of the present study was to analyze the phytochemical composition, antioxidant, and antitumor activities of low-temperature (LT) and high-temperature (HT) aqueous extracts of the cyanobacterium Chroococcus sp. R-10. Extracts were prepared and analyzed for phytochemical composition using UPLC-DAD, and antioxidant activity was tested via multiple assays. Antiproliferative effects were evaluated on human tumor cell lines, and the effects on cell cycle progression studied using flow cytometry. Fluorescence microscopy was employed to examine extract-induced cytomorphological changes in the treated cancer cells. UPLC-DAD analyses showed very similar chromatographic profiles of the extracts and identified glycogen as their main constituent. Both extracts displayed concentration-dependent antioxidant activity, with notable radical scavenging and ferric-reducing capacity. LT extract demonstrated higher phenolic content and antioxidant capacity. Both extracts reduced cell viability, particularly in MCF-7 and MDA-MB-231 breast carcinoma cell lines. Flow cytometry and fluorescent microscopy analyses revealed that the suppressed proliferative activity of the cancer cells was associated with a retardation of cell cycle progression and apoptosis induction. This study identifies Chroococcus sp. R-10 as a promising source of phytochemical compounds with pharmaceutical relevance and provides a rationale for further investigations to identify the primary bioactive constituents and elucidate their mechanisms of anticancer action. Full article

Today, science and medicine are striving to develop novel techniques for treating deadly diseases, including a wide range of cancers. Efforts are being made to better understand the molecular and biochemical mechanisms of tumor cell functioning, but a particular emphasis has recently been given to investigating immune cells residing in the tumor microenvironment, which may lead to revolutionary benefits in the design of new immunotherapies. Among these cells, tumor-associated macrophages (TAMs) are highly abundant and act as critical regulators of ovarian cancer progression, metastasis, and resistance to therapy. Their dual nature—as drivers of malignancy and as potential therapeutic mediators—has positioned them at the forefront of research into next-generation immunotherapies. As therapeutic targets, approaches include blocking macrophage recruitment (e.g., CSF-1/CSF-1R inhibitors), selectively depleting subsets of TAMs (e.g., via Folate Receptor Beta), or reprogramming immunosuppressive M2-like macrophages toward an anti-tumor M1 phenotype. On the other hand, macrophages can also serve as a therapeutic tool—they may be engineered to enhance anti-tumor immunity, as exemplified by the development of Chimeric Antigen Receptor Macrophages (CAR-Ms), or leveraged as delivery vehicles for targeted drug transport into the tumor microenvironment. A particularly innovative strategy involves Macrophage–Drug Conjugates (MDCs), which employs the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular delivery of therapeutic agents, thereby enhancing drug efficacy while minimizing systemic toxicity. This review integrates current knowledge of TAM biology, highlights emerging therapeutic approaches, and underscores the promise of macrophage-based interventions in ovarian cancer. By integrating macrophage-targeting strategies with advanced immunotherapeutic platforms, novel treatment paradigms may be determined that could substantially improve outcomes for patients with ovarian cancer and other solid tumors. Our work highlights that macrophages should be a particular area of research interest in the context of cancer treatment. Full article

Cells of the innate immune system, particularly natural killer (NK) cells, serve as the first line of defense against tumor development and play a critical role in antitumor immunity. Characterizing the immune cell pool and its functional state is essential for understanding immunotherapy mechanisms and identifying key cellular players. However, defining NK cell populations in mice, the primary model for cancer immunotherapy, is challenging due to strain-specific marker variability and the absence of a universal NK cell marker, such as human CD56. This study evaluates surface markers of NK and other peripheral blood immune cells in both humans and mice, associating these markers with specific functional profiles. Bioinformatic approaches are employed to visualize these markers, enabling rapid immunoprofiling. We explore the translational relevance of these markers in assessing immunotherapy efficacy, including their gene associations, ligand interactions, and interspecies variations. Markers compatible with rapid flow-cytometry-based detection are prioritized to streamline experimental workflows. We propose a standardized immunoprofiling strategy for monitoring systemic immune status and evaluating the effectiveness of immunotherapy in preclinical and clinical settings. This approach facilitates the design of preclinical studies that aim to identify predictive biomarkers for immunotherapy outcomes by monitoring immune status. Full article

Grifola frondosa polysaccharides (GFP), which possess antitumor properties, can counteract intestinal injury induced by cyclophosphamide (CTX). The objective of this research was to evaluate the efficacy of GFP in protecting the intestinal barrier of mice and investigate the mechanisms behind this effect. Using a CTX-induced intestinal barrier injury model, we found that GFP treatment significantly alleviated body weight loss and organ atrophy, while enhancing serum IgG and IgM levels. Histological analysis showed that GFP effectively repaired the intestinal mucosal structure, increased goblet cell numbers, and led to an upregulation in the gene expression of ZO-1, Occludin, and MUC2. GFP modulated cytokine expression, including IFN-γ, IL-4, IL-10, and IL-22. According to 16S rDNA sequencing results, GFP enhanced the abundance of unclassified_Muribaculaceae while reducing the prevalence of Escherichia_Shigella. Furthermore, GFP elevated the concentrations of several metabolites, including SCFAs and pyridoxal, which are closely related to intestinal barrier protection and mucosal immunity. Overall, this study demonstrated that GFP has strong potential as an immune-enhancing adjuvant and may represent a promising intervention strategy to mitigate chemotherapy-induced intestinal injury. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor and leads to high human malignancy and mortality. Because PDAC is highly drug-resistant and current treatments have adverse reactions, exploring novel approaches for PDAC prevention and therapy is urgently needed. Methods: Antitumor activities of Salecan were evaluated on multiple human pancreatic adenocarcinoma cells in vitro. Cell viability, colony formation, migration and invasion, flow cytometry, caspase-3 activity, qRT-PCR and Western blotting were monitored. RNA-seq was conducted to clarify the mechanism underlying Salecan’s inhibition of pancreatic cancer cell progression. Results: Here we show that Salecan, a naturally occurring polysaccharide of β-glucan, can significantly inhibit pancreatic cancer cell proliferation and exhibit no toxicity in normal cells. We find that Salecan impedes pancreatic cancer cell migration and invasion via the epithelial-to-mesenchymal transition (EMT) pathway. Mechanistically, through RNA sequencing, we reveal that Salecan induces pancreatic cancer cell necroptosis, instead of apoptosis. Moreover, Salecan’s anti-pancreatic cancer bioactivity is attributed to its promotion of the receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase-like (MLKL) signaling pathway. Conclusions: Salecan can inhibit pancreatic cancer cell proliferation, migration and invasion in vitro and accelerate cell death by inducing the necroptosis via the MLKL/RIPK1 pathway. These findings identify that Salecan may become a potential functional food component for preventing and treating PDAC. Full article

Lotus seed embryos, a key component in traditional Chinese medicine, have attracted growing scientific interest due to their wide-ranging therapeutic potential. Among the bioactive compounds found in lotus seed embryos, three bisbenzylisoquinoline alkaloids—liensinine, isoliensinine, and neferine—stand out for their diverse pharmacological activities. These alkaloids are known to exhibit significant antitumor, anti-inflammatory, antihypertensive, neuroprotective, and antifibrotic effects, which make them promising candidates for the treatment of various chronic and acute diseases. Recent studies have highlighted their ability to modulate key signaling pathways involved in cancer progression, inflammation, fibrosis, and neurodegeneration. The precise mechanisms underlying their actions include modulation of oxidative stress, inhibition of pro-inflammatory cytokines, regulation of apoptosis, and modulation of cellular metabolism. This review aims to provide an in-depth overview of the pharmacological relevance of these alkaloids, focusing on their mechanisms of action and their therapeutic potential across different disease models. By synthesizing current evidence from preclinical studies, this review also lays a solid scientific foundation for future research, supporting the rational design and development of lotus-derived compounds for clinical application. Full article

Even though Pt(II)-based drugs represent the standard in cancer therapy, their use is seriously limited by severe side-effects (renal toxicity, allergic reactions, gastrointestinal disorders, hemorrhage and hearing loss), drug resistance and a grim prognosis. This review presents the results of multiple studies showing different nanoparticle-based platforms as delivery agents in order to overcome these drawbacks. The approach of using nanoparticle-based drug delivery systems of Pt drugs and prodrugs is promising due to key advantages like specific targeting and thereby reduced toxicity to healthy cells; increased stability in the bloodstream; multiple mechanisms of action such as stimulating anti-tumor immunity, responding to environmental stimuli (light, pH, etc.), or penetrating deeper into tissues; enhanced efficacy by their combination with other therapies (chemotherapy, gene therapy) to amplify the anti-tumor effect. However, certain challenges need to be overcome before these solutions can be widely applied in clinics. These include issues related to biocompatibility, large-scale production, and regulatory approvals. In conclusion, using nanoparticles to deliver Pt-based drugs represents an advanced and highly promising strategy to make chemotherapy more effective and less toxic. Nonetheless, further studies are required for the better understanding of intracellular mechanisms of action, toxicity and the pharmacokinetics of nanoparticles, and physical–chemical standardization. Full article