Medical Oncology最新文献

Leukaemia remains a critical haematologic malignancy, where current therapies offer limited efficacy and are frequently associated with significant toxicity. Epigenetic dysregulation, particularly aberrant histone deacetylase (HDAC) activity, promotes uncontrolled proliferation and suppression of apoptosis in leukaemic cells, with HDAC7 identified as a central driver of disease progression. Daidzein, a natural isoflavonoid from Macrotyloma uniflorum, represents a promising plant-derived HDAC inhibitor. This study evaluated daidzein's anti-leukaemic potential using integrated computational, in vitro, and in vivo approaches. Molecular docking and dynamics simulations confirmed stable HDAC7 binding with a binding affinity of -7.6 kcalmol⁻¹, comparable to vorinostat (SAHA; -6.7 kcalmol⁻¹). Daidzein significantly inhibited HL-60 cell viability (IC₅₀ = 19.6 µM) and HDAC activity (IC₅₀ = 3.4 µM), induced apoptosis and G₀/G₁ arrest, and modulated key epigenetic markers by downregulating HDAC7 and enhancing H3K27 acetylation. In vivo, daidzein markedly reduced blast cell burden in blood and bone marrow and alleviated leukaemia-associated hepatic and splenic pathology. HDAC7 suppression was further verified by immunohistochemistry in spleen and liver tissues. Moreover, peripheral blood mononuclear cell profiling showed enhancement of T cells and myeloid cells with concurrent reductions in B cells and macrophages, suggesting immunomodulatory potential.The demonstrated anti-leukaemic and immunomodulatory effects support further investigation toward potential clinical use.

Hepatocellular carcinoma is one of the deadliest cancers occurring worldwide. Substantial evidence suggests that the Hippo-YAP pathway as a promising therapeutic target. Phyllanthus niruri is known for pharmacological activities, including hepatoprotective, anti-viral, and anti-inflammatory effects. However, there is a lacuna of molecular studies on how the bioactives in Phyllanthus niruri interacts with hippo signaling to enhance its potential for liver cancer management. This study aimed to delineate the effects of Phyllanthus niruri extract on cell proliferation and apoptosis, and its mechanisms in modulating the Hippo-YAP signaling, using Huh-7 cells and a diethylnitrosamine-induced liver cancer model in Wistar rats. MTT assay results confirmed that Phyllanthus niruri reduced the viability of Huh-7 cells in a dose-dependent manner. Notably, Phyllanthus niruri extracts decreased nuclear YAP-localization by modulating upstream regulators of the Hippo-YAP pathway and promoted apoptosis, as evidenced by increased ROS levels and the upregulation of Bax and downregulation Bcl-2 protein expression. In diethylnitrosamine-induced liver cancer rats, oral administration of Phyllanthus niruri extract significantly reduced tumor burden, activated hippo signaling, and exhibited therapeutic effects. Overall, Phyllanthus niruri extracts exhibited anti-proliferative, and pro-apoptotic effects in experimental liver cancer models offering valuable insights into their mechanism of action through modulation of the Hippo-YAP signaling pathway.

HCC is characterized by extensive ECM remodeling, primarily mediated by stromal cells. While cancer-associated fibroblasts are known contributors to tumor fibrosis, their transcriptional diversity and role in immune modulation within the HCC tumor microenvironment remain poorly resolved. Integrative analysis of six public HCC scRNA-seq datasets was employed to identify ECM-active stromal cells. High-ECM cells were re-clustered and fibroblast subtypes were defined through differential expression, pathway enrichment, lineage scoring and cell-cell interaction modeling. Spatial transcriptomic mapping and tissue-level profiling were performed to validate and prioritize ECM-related genes for experimental analysis. COL1A1 and COL3A1 were selected for siRNA-mediated knockdown in HepG2 and HepB3 cells followed by RT-qPCR, Western blot, proliferation, colony formation and wound healing assays. ECM activity analysis identified fibroblasts as the most ECM-enriched stromal population. Reclustering of ECM-high stromal cells identified eight distinct subtypes and targeted fibroblast clustering revealed five functionally diverse states. GO and spatial transcriptomic analysis confirmed subtype-specific functions and localization. In silico tissue profiling further prioritized COL1A1 and COL3A1 as pan-mesenchymal ECM genes enriched in fibrogenic fibroblast subsets. CellChat analysis revealed myofibroblasts and inflammatory CAFs as dominant signal senders. Knockdown reduced COL1A1 and COL3A1 expression at both mRNA and protein levels, and enhanced HCC cell proliferation, migration and colony formation. This study identifies transcriptionally and functionally distinct fibroblast subtypes in HCC and highlights COL1A1 and COL3A1 as key matrix-regulatory genes expressed in fibrogenic stromal subsets.

Pancreatic ductal adenocarcinoma (PDAC) is usually treated with gemcitabine (GEM)-based chemotherapy. However, resistance to GEM develops frequently. Aberrant fibroblast growth factor receptors (FGFR) signaling in PDAC is linked to advanced tumor stages and poor prognosis, making it a potential therapeutic target. This study aimed to explore whether inhibition of FGFR by derazantinib could reduce the resistance to GEM in PDAC. Human AsPC-1 and BxPC-3 PDAC cell lines were screened against a panel of FDA-approved compounds to identify the potential drug. Gem-resistant cell lines were subsequently utilized to validate the efficacy of derazantinib. The synergistic interaction between derazantinib and GEM was confirmed through combination-index analysis, clonogenic assays, and apoptosis assays. With RNA-seq, immunohistochemistry, Western blotting, and animal experiments, the effects of derazantinib on the malignant behaviors, signaling pathways in GEM-resistant PDAC cells and tumors were examined. Treatment with derazantinib and GEM synergistically inhibited the malignant behaviors of GEM-resistant PDAC cells and tumor growth by downregulating FGFR2 and FGFR3 expression. RNA-seq revealed upregulated MUC5AC expression in GEM-resistant PDAC, which was attenuated by derazantinib through inhibiting the MAPK and NF-κB signaling. Furthermore, higher levels of FGFR2 and FGFR3 expression were associated with worse survival of PDAC patients and negatively correlated with tumor differentiation. Moreover, the combination of derazantinib and GEM significantly inhibited the growth of GEM-resistant PDAC tumors in vivo. The data highlighted that higher levels of FGFR2, FGFR3, and MUC5AC expression promoted the progression and resistance to GEM in PDAC. Derazantinib treatment enhanced the sensitivity to GEM by attenuating the NF-κB and MAPK pathways to inhibit MUC5AC expression. Therefore, derazantinib may be a promising chemotherapeutic adjuvant for treating PDAC, particularly for patients with GEM resistance.

Hepatocellular carcinoma (HCC) continues to be a significant cancer in India, exhibiting a yearly incidence of about 1.6%. The limitations of conventional chemotherapy, such as systemic toxicity and drug resistance, highlight the need of natural chemosensitizers in improving therapeutic outcomes. This study assesses the chemosensitizing ability of Black Grape Anthocyanins (BGA) derived from the Manjari Medika (MM) grape variety to improve the efficacy of low-dose 5-Fluorouracil (5-FU) in HepG2 cells. MM grapes are high in polyphenols and contains 12 different anthocyanin derivatives, as determined by Liquid Chromatography-Mass spectrometry (LC-MS) analysis. HepG2 cells were treated with varying concentrations of 5-FU and BGA, both alone and in combination, and their viability, ROS generation, mitochondrial integrity, calcium influx, apoptosis, and autophagy indicators were measured using biochemical and imaging methods. Co-treatment with 5-FU (50 µM) and BGA (80 µg/ml) significantly increased cytotoxicity compared to individual therapies. The combination caused significant cytosolic calcium influx as well as enhanced intracellular and mitochondrial reactive oxygen species (ROS), resulting in mitochondrial depolarisation and structural disintegration. These changes stimulated intrinsic apoptotic signalling, as evidenced by higher Bax and cleaved Caspase-3 expression and lower Bcl-2 levels. Autophagic flux increased concurrently, as demonstrated by overexpression of LC3A/B and Beclin 1 (2.36 and 1.27-fold, respectively). ROS scavenging with NAC reduced these effects, establishing ROS as an important upstream mediator. Importantly, BGA showed little cytotoxicity in primary hepatocytes. Overall, BGA works as a strong, selective chemosensitiser that improves 5-FU efficacy via ROS-mediated regulation of calcium signalling, apoptosis, and autophagy in HCC cells.

Ovarian cancer is among the deadliest gynecological malignancies due to its aggressive nature and limited treatment options. Mebendazole (MBZ), a known antiparasitic drug, has shown anticancer activity in several cancer types, though its mechanisms, particularly in ovarian cancer, remain unclear. Girdin (CCDC88A), a key regulator of Akt signaling and cancer cell invasion, represents a promising therapeutic target. This study explores the combined effect of MBZ and Girdin knockdown in ovarian cancer cell lines OVCAR3 and OAW42. Cells were treated with MBZ and transfected with Girdin-targeting siRNA, either individually or in combination. Biochemical assays (migration, invasion, and clonogenicity) and immunoblotting were used to assess the molecular mechanism and protein expression. Computational techniques, including homology modeling, molecular docking, structural interaction fingerprinting (SIFt), and density functional theory (DFT), were employed to study MBZ-Girdin binding. In addition, protein-protein interaction (PPI) network analysis and KEGG pathway enrichment (visualized using Cytoscape) were conducted to understand broader molecular effects. Our results showed that both MBZ and Girdin knockdown significantly decreased Girdin levels, with the combination yielding a greater inhibitory effect. This dual approach led to marked suppression of ovarian cancer cell migration, invasion, and colony formation. Docking studies confirmed stable MBZ binding to Girdin's catalytic domain, supported by favorable binding energies and molecular interactions. This is the first study to demonstrate that MBZ's anticancer efficacy is significantly enhanced by Girdin silencing, implicating the modulation of critical oncogenic pathways.

Ethanol was previously classified as a co-carcinogen or tumour promoter, based on early animal studies. Ethanol may also contribute to cancer development indirectly by serving as a solvent for chemical constituents found in tobacco smoke, fried meals that contain N-nitrosodiethylamine (NDEA), led to increased production of reactive oxygen species (ROS), inflammation, fibrosis, enhanced cell proliferation, and the development of hepatocellular carcinoma (HCC). Approximately 70% of anticancer agents are derived from plant-based sources. This study was designed under in silico, in vitro, and in vivo sections, using HPTLC, LC-MS, ELISA techniques and the experiments were performed with lyophilised methanolic fruit extract residue of Morinda citrifolia (MFER-Mc) to treat alcohol and NDEA (200 mg/kg b.w., i.p.) induced HCC in Wistar albino male rats. The tyrosinase inhibitory activity observed in M. citrifolia, is associated with the lignans present, particularly 3,3'-bisdemethylpinoresinol and Americanin-A. Liver X receptors (LXRs) have recently been identified as anti-inflammatory transcription factors capable of modulating a variety of physiological processes. MFER-Mc directly interacts with molecular targets like LXR-beta, LXR-alpha, and HMG-CoA reductase to restore metabolic homeostasis and lessen carcinogenic disruptions brought on by exposure to alcohol and NDEA. To maximise benefit for patients with liver cancer and improve translation into clinical use, more research addressing pharmacokinetics, clinical efficacy, and treatment combinations is necessary.

Ovarian cancer (OC) is the most lethal gynecologic malignancy due to late-stage diagnosis, frequent recurrence, and resistance to therapy. Emerging evidence highlights oxidative stress (OS)-a redox imbalance caused by excessive reactive oxygen species (ROS)-as a key contributor to tumor development and therapy failure. This article presents a narrative review of the bidirectional relationship between oxidative stress and microRNAs (miRNAs) in OC, emphasizing their molecular crosstalk, clinical relevance, and therapeutic potential. A targeted synthesis of recent experimental and clinical studies was conducted to explore how redox biology and miRNA dysregulation contribute to OC pathogenesis and treatment resistance. ROS promotes genomic instability, epithelial-mesenchymal transition (EMT), angiogenesis, immune evasion, and chemoresistance. Redox-responsive miRNAs (e.g., miR-29b, miR-200a/c, miR-145-5p, miR-484, miR-21) regulate antioxidant defenses, DNA repair, apoptosis. OS modulates miRNA biogenesis via transcriptional and epigenetic changes, and miRNAs form feedback loops that influence ROS levels and tumor progression. Circulating and exosomal miRNAs show promise as non-invasive biomarkers, but require further clinical validation. Therapeutic approaches targeting the ROS-miRNA axis-including mimics, antagomiRs, and nanocarriers-show preclinical potential, though challenges in delivery and toxicity remain. The dynamic OS-miRNA interplay represents a novel regulatory axis in OC. Exploiting this axis may enhance early diagnosis and therapy. Future work should integrate redox profiling with miRNA expression to personalize treatment and assess performance relative to existing modalities like PARP inhibitors.

Breast cancer is one of the cancers with the highest incidence among women worldwide. Increasing evidence suggests that the long noncoding RNA cytoskeleton regulator (CYTOR) plays a critical role in cancers and is upregulated in many cancer types. In this study, the effects of siRNA inhibition of CYTOR, a long non-coding RNA (LncRNA), on cell viability, apoptosis, Hippo signaling pathway and molecular mechanisms involved in metastasis were investigated in breast cancer cell lines. The suppressive effects of CYTOR on cell proliferation in MDA-MB-231 and HCC1428 cells were determined by the 3-(4,5-Dimethyltriazol-2-yl)-2.5 diphenyltetrazolium bromide (MTT) method. Scratch assay, colony formation assay, migration and invasion tests, were performed to determine the effects of CYTOR on the proliferation and migration of MDA-MB-231 and HCC1428 cells. In addition, its effects on apoptotic (Bax, Bcl-2), Hippo and metastatic genes (YAP1, MST1, LATS1, CTGF, ECAD, NCAD) were determined using quantitative real-time polymerase chain reaction (qRT-PCR). As a result of the study, CYTOR expression was suppressed by 80% with siCYTOR-779 in MDA-MB-231 cells and by 88% with siCYTOR-572 in HCC1428 cells. The CYTOR suppression significantly inhibited cell proliferation, cell colony formation and migration of breast cancer cells. It was also determined that CYTOR suppression caused a decrease in the expression of the YAP1 gene, a key effector of the Hippo signaling pathway and the CTGF gene, one of its target genes. In conclusion, our findings suggest that CYTOR may be a potential therapeutic target in breast cancer by regulating the Hippo signaling pathway.

The accurate control of immune responses in the tumor microenvironment is crucial for augmenting anti-cancer immunity. This work examined the function of STAT3 in modulating epigenetic and epitranscriptomic pathways during the differentiation of CD4 + T helper cells in non-small cell lung cancer (NSCLC). Employing CRISPR/Cas9 genome editing, STAT3 was specifically eliminated in CD4⁺T cells derived from NSCLC patients. Functional investigations demonstrated that the reduction of STAT3 markedly enhanced the production of T helper 1 (TH1) cytokines, notably IFN-γ, while concurrently diminishing immunosuppressive signaling. Epigenetic analysis revealed significant modifications in DNA and RNA methylation patterns, along with heightened R-loop formation-alterations linked to augmented transcriptional activity of anti-tumor immune genes. Moreover, STAT3-deficient CD4⁺T cells demonstrated an enhanced ability to activate cytotoxic T lymphocytes, facilitating the targeted eradication of tumor cells. All of these effects together made the NSCLC microenvironment's immune system better at fighting cancer. Our results identify STAT3 as a crucial regulator of the genetic and epigenetic frameworks that influence T cell functionality in lung cancer. By combining RNA-guided genome editing with immune functional tests, we show that blocking STAT3 in a specific way could bring back strong anti-tumor immunity. This research underscores the therapeutic potential of STAT3-targeted therapies, presenting an innovative approach to alter T cell destiny and improve immune-mediated tumor eradication in non-small cell lung cancer (NSCLC). These methods could lead to the next generation of immunotherapies that improve clinical outcomes by fine-tuning both epigenetic and epitranscriptomic circuits.