Medical Oncology最新文献

The development of drug resistance remains a major obstacle in the treatment of metastatic melanoma, necessitating novel therapeutic strategies. Combining natural compounds with agents that disrupt cancer cell survival mechanisms, such as autophagy inhibitors, offers a promising approach. This study aimed to evaluate the potential synergy between the plant-derived monoterpene carvacrol and the autophagy inhibitor chloroquine against metastatic melanoma. The cytotoxic and proapoptotic effects of carvacrol, chloroquine, and their combination were investigated in the WM9 metastatic melanoma cell line using WST-1 assays and Annexin V/7-AAD flow cytometry. The nature of the drug interaction was quantified using the Q-value. In silico molecular docking was performed to identify potential protein targets and elucidate the mechanisms underlying the observed effects. While carvacrol monotherapy exhibited weak cytotoxicity, its combination with non-toxic concentrations of chloroquine resulted in a potent and synergistic reduction in WM9 cell viability. This enhanced cytotoxicity was attributed to a significant, synergistic induction of apoptosis. In silico analysis predicted that both carvacrol and chloroquine bind with high affinity to common molecular targets, including Insulin-Like Growth Factor 1 Receptor and Sirtuin-2. Chloroquine was also predicted to interact strongly with HSP90. Our findings demonstrate that chloroquine potentiates the anticancer activity of carvacrol in metastatic melanoma cells. The synergy observed is likely mediated by a multi-targeted mechanism involving the simultaneous disruption of key cancer survival and signaling pathways. This study establishes the carvacrol-chloroquine combination as a novel and effective strategy that warrants further preclinical investigation for the treatment of resistant melanoma.

Gefitinib Resistance (GR) is a frequent occurrence for non-small cell lung cancer (NSCLC). Here, we aim to explore a novel miR-101-3p shuttled by NSCLC cells in the growth and metastasis of NSCLC cells. Real-time PCR was performed to assess the level of miR-101-3p in cells and exosomes derived from the NSCLC cells. Effect of miR-101-3p on cell proliferation, metastasis and gefitinib sensitivity was then detected. Instinctively, METTL14 expression level was detected, which was positively related to that of miR-101-3p. Function of METTL14 on cell proliferation and metastasis was also investigated. High level of exosomal and intracellular miR-101-3p is correlated with better gefitinib response. miR-101-3p inhibited NSCLC cell proliferation and migration. In terms of mechanism, METTL14 endow NSCLC cells with gefitinib sensitivity via intracellular and exosomal miR-101-3p, leading to modulating of GSK-3β/Akt pathway. Collectively, this study indicated that restored METTL14/miR-101-3p confers gefitinib sensitivity in GR NSCLC by targeting GSK-3β/Akt pathway, indicating METTL14/miR-101-3p may act as a potential biomarker and therapeutic target for gefitinib response in NSCLC.

This study aimed to investigate the potential of Venetoclax combined with ML385 to overcome drug resistance in leukemia cells and the related mechanisms. Analysis of Nrf2 expression and its prognostic significance in AML was performed utilizing the GEO and GEPIA2 databases. Bone marrow specimens were collected from newly diagnosed AML patients to evaluate Nrf2 expression levels and assess their correlation with established risk stratification and clinical prognosis. Two doxorubicin-resistant leukemia cell lines were established. Subsequently, stable Nrf2-knockdown cell lines were generated via lentiviral transduction. Cellular proliferation and apoptosis were analyzed. Levels of reactive oxygen species (ROS) and glutathione (GSH), alongside the expression of oxidative stress-related and apoptosis-related genes and proteins, were quantified. Furthermore, the effects of Venetoclax combined with ML385 on proliferation, apoptosis, ROS levels, and GSH levels were subsequently investigated in these doxorubicin-resistant cell lines. Mechanistically, the impact of the drug combination on oxidative stress and the PI3K/AKT signaling pathway was explored. Nrf2 was up-regulated in AML and predicted poor prognosis. In doxorubicin-resistant AML cells, oxidative-stress genes were elevated. Silencing Nrf2 inhibited proliferation, induced apoptosis, lowered GSH, raised ROS, increased pro-apoptotic BAX and Caspase-3, and decreased anti-apoptotic Bcl-2. Combining the venetoclax with ML385 significantly suppressed proliferation and induced apoptosis in drug-resistant leukemia cells. Mechanistically, this dual-targeting regimen concurrently attenuated both the Nrf2-mediated antioxidant defense and the pro-survival PI3K/AKT signaling axis, which collectively underpin its enhanced anti-leukemic efficacy. This study demonstrates venetoclax combined with ML385 overcomes chemotherapy resistance in acute myeloid leukemia by modulating Nrf2/ARE-mediated oxidative stress.These findings reveal a novel mechanism and a promising therapeutic strategy.

Recent advances in Medical Oncology highlight the integration of bulk and single-cell transcriptomics to reveal glycolytic heterogeneity in colorectal cancer. Translating these discoveries into reliable clinical tools requires rigorous methods, transparent validation, and equity-minded implementation. This communication proposes a standards-first roadmap for reproducible and globally relevant biomarker development. It identifies major technical pitfalls such as batch-effect over-correction and normalization bias, and recommends the application of internationally recognized frameworks-TRIPOD + AI, PROBAST + AI, and DECIDE-AI-to ensure transparency, calibration, and staged clinical evaluation. Orthogonal validation using metabolic imaging and spectroscopy is emphasized to confirm biological realism beyond transcriptomic data. The roadmap concludes with strategies for global equity, including LMIC-inclusive trial design, FAIR data standards, and cost-aware clinical surrogates. This structured approach bridges discovery science with practical implementation, aligning precision oncology with reproducibility, accountability, and global accessibility.

Advanced oesophageal neuroendocrine carcinoma (ENEC) is a highly aggressive and rare malignancy with poor prognosis. Due to the rarity of this cancer there are currently no standardised treatment regimens for ENEC, and models to study this disease are difficult to obtain. To address this, we screened our established circulating tumour cell line from a patient with metastatic ENEC, termed UWG01CTC, using the LOPAC^®1280 drug repurposing library. The redox modulatory agent adaphostin was identified as a potent cytotoxin against UWG01CTC but not non-ENEC cell lines. Secondary adaphostin cell viability screens returned IC₅₀ values of 0.201 ± 0.024 µM confirming the high sensitivity of this ENEC CTC line to the drug. Inclusion of the antioxidant N-acetyl cysteine significantly protected the UWG01CTCs against the cytotoxic effects of adaphostin (IC₅₀ = 0.928 ± 0.425 µM), corroborating a mechanism mediated through the generation of reactive oxygen species (ROS). The expression of DNA damage marker phospho-γH2AX and apoptotic marker cleaved PARP1 were both elevated in cells treated with adaphostin, suggesting that the increased intracellular ROS levels induced by the drug causes downstream DNA damage and ultimately apoptosis. Thus, adaphostin shows promise as a potential new and selective treatment for ENEC.

Colorectal cancer (CRC) is one of the most prevalent and deadliest cancers worldwide. Despite current treatments, therapeutic resistance remains a paramount challenge. Glycoproteins play essential roles in cellular processes and have been linked to drug resistance in CRC. This scoping review aims to synthesise the existing evidence on the role of glycoproteins in regulating apoptosis and autophagy in colorectal cancer. A comprehensive search was conducted using the keywords ("Autophagy") AND ("Apoptosis ") AND ("glycoprotein" OR "glycosylated proteins") AND ("colorectal cancer" OR "colon cancer" OR "CRC") across PubMed, Web of Science, and Scopus databases on 1 May 2025 without restriction. A total of nine English-language original articles were included. The outcomes show that glycoproteins such as P-gp and MRP-1 are often overexpressed in CRC cells. Inhibition of these glycoproteins significantly reduces their expression and the proliferation of CRC cells, while also enhancing cell death via apoptosis and autophagy. Hence, regulating glycoproteins in CRC provides a novel strategy to inhibit cancer progression, offering a potential avenue to overcoming therapy resistance in CRC. However, further in vivo research is necessary to elucidate the mechanism of action of glycoproteins.

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.