Anti-cancer agents in medicinal chemistry最新文献

{"title":"Efficacy and Safety of HAIC Plus Regorafenib and Icaritin in Advanced Hepatocellular Carcinoma After First-Line Lenvatinib Failure: A Retrospective Analysis.","authors":"Haohao Lu, Ya Gao, Bin Liang, Dongqiao Xiang, Xiangwen Xia","doi":"10.2174/0118715206464057260629115247","DOIUrl":"https://doi.org/10.2174/0118715206464057260629115247","url":null,"abstract":"<p><strong>Introduction: </strong>We evaluated the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with regorafenib and icaritin in patients with advanced hepatocellular carcinoma (HCC) progressing after first-line lenvatinib therapy, based on retrospective observational data, with the goal of proposing a novel second-line strategy to improve survival outcomes.</p><p><strong>Materials and methods: </strong>A retrospective analysis included 79 advanced HCC patients treated at Union Hospital between January 2022 and October 2023, all with confirmed progression after first-line lenvatinib. Participants were divided into two groups: HAIC + regorafenib + icaritin (n=38) and regorafenib monotherapy (n=41). Primary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). Secondary endpoints covered changes in blood biomarkers and treatment-related adverse events (AEs).</p><p><strong>Results: </strong>The triple-therapy group demonstrated superior ORR (44.7% vs. 19.5%, P<0.05) and DCR (73.7% vs. 48.8%, P<0.05) compared to monotherapy. Median PFS (6.7 vs. 3.9 months, P<0.05) and median OS (12.4 vs. 9.2 months, P<0.05) were significantly prolonged with combination therapy. Although all-grade abdominal pain, fever, and vomiting were more frequent in the triple-therapy group (P<0.05), the incidence of grade 3/4 AEs did not differ significantly between groups. Notably, all-grade fatigue was less common in the combination group (P<0.05).</p><p><strong>Discussion: </strong>The survival benefit with triplet therapy likely reflects complementary mechanisms: HAIC delivers high intratumoral drug concentrations, thereby bypassing local resistance; regorafenib blocks bypass signaling pathways upregulated after lenvatinib failure; and icaritin reduces fatigue through immunomodulation. While safety is manageable, the retrospective design limits causal inference, highlighting the need for prospective validation.</p><p><strong>Conclusion: </strong>HAIC combined with regorafenib and icaritin shows enhanced efficacy and manageable toxicity in lenvatinib-refractory advanced HCC, with improved physical tolerance evidenced by reduced fatigue. The observed benefits of this triplet regimen warrant further prospective validation as a potential personalized secondline approach for Barcelona Clinic Liver Cancer stage C (BCLC-C) patients, pending confirmation in randomized controlled trials.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.","authors":"Qasim Javed, Shoaib Majeed, Adnan Shahid, Naheed Bano, Bushra Munir, Mohanad W Mahdi Alzubadiy, Esha Mustafa, Sara Siddique, Magda H Abdellattif, Alaa Abu Alnjaa, Ajmal Khan, Ahmed Al-Harrasi","doi":"10.2174/0118715206422827251203222619","DOIUrl":"https://doi.org/10.2174/0118715206422827251203222619","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Efficacy of Poly-ADP-Ribose Polymerase Inhibitors (Parpis) in the Treatment of Advanced Ovarian Cancer in Younger and Elderly Patients: A Systematic Review and Meta-Analysis.","authors":"Yujie Feng, Ying Zhang, Juanjuan Hu, Yuchen He, Jiayun Liu","doi":"10.2174/0118715206456542260612060505","DOIUrl":"10.2174/0118715206456542260612060505","url":null,"abstract":"<p><strong>Introduction: </strong>To compare the efficacy of PARPIs in younger and elderly patients with advanced ovarian cancer.</p><p><strong>Methodology: </strong>This meta-analysis was conducted according to PRISMA guidelines. Study selection was performed using predefined inclusion and exclusion criteria. Pooled estimates were calculated as hazard ratios (HRs) with 95% confidence intervals. Between-study heterogeneity was assessed using the I² statistic. Publication bias was evaluated visually using funnel plots. A leave-one-out sensitivity analysis was performed to assess the influence of individual studies on the overall results.</p><p><strong>Results: </strong>PARPIs showed a significant improvement in progression-free survival compared to non-PARPIs in both elderly and younger patients, with pooled HRs of 0.54 (0.45-0.65) for elderly patients and 0.45 (0.36-0.58) for younger patients. Heterogeneity among studies was higher in younger patients than in elderly patients, as indicated by the I² values. Funnel plot assessment suggested minimal publication bias.</p><p><strong>Discussion: </strong>Overall, the findings support that PARPIs improve progression-free survival in both age groups. However, heterogeneity was higher in younger patients, and the age subgroup findings are based on secondary subgroup data from clinical trials; therefore, the results should be interpreted cautiously.</p><p><strong>Conclusion: </strong>PARPIs demonstrate a significant clinical benefit in advanced ovarian cancer in both elderly and younger patients, mainly by improving progression-free survival.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, Spectroscopic Analysis, and In Silico Molecular Docking Study of Novel Azo Compounds as Potential Antioxidant and Anti-Triple-Negative Breast Cancer Agents.","authors":"Zainab Y Kadhim, Hasanain Gomhor J Alqaraghuli, Ali Y Naoom, Mohammed Kassim Al-Hussainawy, Hussein A K Kyhoiesh","doi":"10.2174/0118715206469924260605050704","DOIUrl":"https://doi.org/10.2174/0118715206469924260605050704","url":null,"abstract":"<p><strong>Introduction: </strong>The aim of this study was to synthesize novel bioactive azo compounds and investigate their anti-triple-negative breast cancer and antioxidant properties using in vitro and in silico approaches.</p><p><strong>Methods: </strong>The structures of the synthesized azo derivatives were confirmed using FT-IR, NMR (¹H and ¹³C), EIMS spectroscopy, TGA, and CHN analyses. The anticancer activity of the azo compounds was evaluated using both TNBC cells (MDA-MB-231) and non-tumorigenic cells (MCF-10A). Molecular docking experiments were conducted to improve our understanding of how the azo compounds interact with and bind to the EGFR receptor. Additionally, antioxidant activity and hemolysis studies were performed.</p><p><strong>Results: </strong>The IC₅₀ values (μg/mL) for MDA-MB-231 cell viability following treatment with AZ1, AZ2, AZ3, AZ4, and adriamycin were 31.2, 18.4, 32.6, 37.7, and 20.1, respectively. However, the synthesized compounds exhibited low toxicity toward MCF-10A cells at concentrations of 50 μg/mL or less, with cell viability remaining above 80%. The IC₅₀ values (μg/mL) for the DPPH● scavenging activities of compounds AZ1, AZ2, AZ3, and AZ4, as well as ascorbic acid, were 94.79, 66.32, 134.2, 148.79, and 46.76, respectively.</p><p><strong>Discussion: </strong>The azo compound AZ2 effectively inhibits MDA-MB-231 cell proliferation due to its strong affinity for the EGFR receptor, which is known to be overexpressed in TNBC cells, as confirmed by docking studies.</p><p><strong>Conclusion: </strong>The positive results of the hemolysis study indicate that these compounds are hemocompatible with hRBCs at the concentrations used in this study. This finding makes AZ2 a promising candidate for use as an anti- TNBC agent.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology-Empowered Photodynamic Therapy for Improved Oral Cancer Treatment.","authors":"Venkateshwaran Krishnaswami, Selvakumar Muruganantham, Jacob Raja, Saravanakumar Arthanari","doi":"10.2174/0118715206429912251215100714","DOIUrl":"https://doi.org/10.2174/0118715206429912251215100714","url":null,"abstract":"<p><strong>Background: </strong>Oral cancer is the most prevalent type of head and neck cancer, usually affecting those 60 years of age and older. Oral cancer affects the lips and the first few sections of the tongue. Oral cancer has the potential to spread to other parts of the head and neck if treatment is not received. The oral cavity's squamous cells are where oral cancer begins. The Photodynamic Therapy (PDT) has emerged as a promising therapeutic modality due to its effectiveness, selectivity, and minimal invasiveness.</p><p><strong>Methods: </strong>To provide updated information, a review was conducted by searching electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar up to December 2024. Keywords such as \"Oral cancer\", \"Photodynamic therapy\", and \"Photosensitizer\" were employed to retrieve relevant literature, with emphasis placed on original research articles, reviews, and clinical studies. The selection criteria focused on recent advancements in PDT and nanotechnology applications for oral cancer.</p><p><strong>Results: </strong>The review highlights the use of synthetic and natural photosensitizers in PDT for oral cancer. Recently, nanotechnology has led to the development of nanformulated photosensitizers with improved safety as well as therapeutic efficacy.</p><p><strong>Conclusion: </strong>PDT involves administering a photosensitizer-based light-sensitive medication, followed by exposure to laser light at a specific wavelength that targets the photosensitizer's absorption maxima. This may induce singlet oxygen and target diseased cells. With an emphasis on innovative photosensitizer-based nano formulations, this study focuses on the state of knowledge on PDT's uses in the treatment of oral cancer. The review emphasizes the promising role of nanotechnology-enhanced PDT as a minimally invasive and targeted approach for oral cancer therapy. It also addresses the role of oral microbiota, current challenges, and prospects. Overall, nano-PDT shows strong potential to improve outcomes and reduce recurrences.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plant-Derived Polyphenols in the Fight against Colorectal Cancer.","authors":"Carely Arjona-Ruiz, Eduardo E Valdez-Morales, Raquel Guerrero-Alba","doi":"10.2174/0118715206464523260604100319","DOIUrl":"https://doi.org/10.2174/0118715206464523260604100319","url":null,"abstract":"<p><strong>Introduction: </strong>Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of cancer-related mortality. Despite advances in surgery, chemotherapy, and targeted therapies, many CRC patients experience limited efficacy, toxicity, or drug resistance. Thus, complementary therapeutic strategies with an improved safety profile are needed. Plant-derived polyphenols emerge as promising candidates for CRC treatment.</p><p><strong>Methods: </strong>This review compiles in vitro, in vivo, and clinical evidence on the anticancer activity of polyphenols in CRC. Polyphenols, such as curcumin, resveratrol, quercetin, and flavonoids, are analyzed, with emphasis on molecular mechanisms and chemopreventive potential.</p><p><strong>Results: </strong>In vitro studies consistently demonstrate that these compounds exert anticancer effects by modulating multiple pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, STAT3, and MAPK/ERK, promoting apoptosis and regulating oxidative stress and inflammation. In vivo studies indicate that curcumin, resveratrol, quercetin, epigallocatechin gallate (EGCG), genistein, luteolin, and fisetin significantly reduce tumor volume, polyp formation, and aberrant crypt foci (ACF). Curcumin has been extensively evaluated in trials, with some studies demonstrating reductions in ACF and improvements in inflammatory markers and quality of life, while others have demonstrated no significant clinical benefit.</p><p><strong>Discussion: </strong>Preclinical evidence supports the chemopreventive role of polyphenols. Preliminary clinical trials also suggest therapeutic potential for CRC prevention and treatment; however, large-scale, well-controlled clinical trials are required to confirm their safety and efficacy.</p><p><strong>Conclusion: </strong>Plant-derived polyphenols represent promising complementary strategies for CRC prevention and therapy. Future research should prioritize compounds with strong preclinical evidence, standardized formulations, optimized delivery strategies, and rigorously designed randomized trials to facilitate integration into clinical oncology practice.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Frontiers in Nanomedicine for Colorectal Cancer: A Review of Therapeutic Advances, Clinical Evidence, and Patented Technologies.","authors":"Dushyant, Smita Narwal, Gurvirender Singh, Ashwani K Dhingra, Jasmeen Kaur, Balram, Nisha Grewal","doi":"10.2174/0118715206393645251127150335","DOIUrl":"https://doi.org/10.2174/0118715206393645251127150335","url":null,"abstract":"<p><strong>Introduction: </strong>Colorectal cancer (CRC) is the third most prevalent cancer globally, and metastatic CRC is almost always fatal. Early stages (0 to III) of CRC are generally curable, but Stage IV CRC is typically not curable and can only be controlled depending on the extent of disease spread. The objective of the current study is to discuss efficient targeted drug delivery systems for CRC and critically assess recent advancements in nanotechnology-based drug delivery.</p><p><strong>Methods: </strong>A critical review of the literature was conducted, including patent and clinical trial analyses on nanotechnology-based drug delivery systems for CRC. The research aimed to evaluate new nanocarriers such as dendrimers, liposomes, carbon nanotubes, and nanoemulsions.</p><p><strong>Results: </strong>Nanotechnology-based novel drug delivery systems were identified as more specific for targeting CRC cells. These technologies have been shown to exhibit greater cellular uptake, improved pharmacokinetics, and enhanced overall efficacy of anticancer drugs. Evidence from clinical trials and patent statistics reaffirms the potential of nanomedicines to revolutionize CRC therapy by increasing drug specificity and reducing systemic toxicity.</p><p><strong>Discussion: </strong>The findings indicate the enormous potential of nanotechnology to improve CRC therapy through better drug targeting and fewer side effects. The results are consistent with the growing body of literature supporting the integration of nanocarriers into oncology. Despite challenges such as the need for validation in clinical settings and the translation of laboratory successes into conventional medical practice, continued efforts are essential to make effective cancer treatment a reality without causing harm.</p><p><strong>Conclusion: </strong>Nanotechnology-based drug delivery systems have significant therapeutic potential in the management of CRC by maximizing treatment efficacy and minimizing side effects. Additional research and clinical data are needed to establish these systems as an integral part of routine clinical practice.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microfluidic Synthesis of miR-10a Antisense Oligonucleotides-Loaded LNP Combined with Cisplatin for Colorectal Cancer Therapy.","authors":"Shaorong Li, Jinzhuai Li, Hongmian Jiang, Kun Zhao, Lifeng Luo, Huali Huang, Zhijie Liang","doi":"10.2174/0118715206425945251202115825","DOIUrl":"https://doi.org/10.2174/0118715206425945251202115825","url":null,"abstract":"<p><strong>Introduction: </strong>To address the issue of insufficient sensitivity of the chemotherapeutic drug cisplatin in colorectal cancer (CRC), this study aimed to develop a miR-10a antisense oligonucleotide (AMO) system delivered by lipid nanoparticles (LNPs). The aim was to enhance the sensitivity and efficacy of cisplatin by targeting and inhibiting the expression of miR-10a in CRC.</p><p><strong>Methods: </strong>Through bioinformatics analysis, key miRNAs that are differentially expressed in colon cancer were identified. Then, by using the FDA-approved patisiran formulation and microfluidic technology, LNPs/miR10a- AMOs were constructed to target miR-10a. The transfection efficiency, anti-tumor effectiveness, and safety were evaluated through in vivo and in vitro experiments.</p><p><strong>Results: </strong>LNPs increased the transfection efficiency of AMOs by 2.3 times (p < 0.01). In HCT116 cells, miR- 10a expression was inhibited by 68.5%, and after combined treatment with cisplatin, the IC50 decreased from 8.7 μM to 5.0 μM (p < 0.001). Meanwhile, cell viability in normal THLE2 and HCoEpiC cells remained > 85%. In the xenograft model, the combined therapy achieved a 100.4% tumor growth inhibition compared to cisplatin monotherapy, with Ki67 expression decreased by 67.3%, and cleaved-caspase-3 expression increased by 3.1- fold (p<0.001). Histopathological analysis confirmed minimal organ toxicity. Mechanistically, miR-10a downregulation sensitized the tumor by activating the apoptotic pathway and inhibiting proliferation.</p><p><strong>Discussion: </strong>Our findings demonstrated that targeting miR-10a significantly enhanced the sensitivity of tumor cells to cisplatin, providing a novel strategic approach to overcome chemoresistance. Compared to existing studies, the innovation of this work lies in employing an FDA-approved LNP formulation, substantially improving the feasibility for clinical translation. Furthermore, the application of microfluidic technology ensured reproducible nanoparticle preparation, offering distinct advantages over conventional methods in terms of industrial applicability. However, this study has involved certain limitations; the animal models utilized could not fully recapitulate the complexity of the human tumor microenvironment, and the precise molecular mechanisms regulated by miR-10a warrant further investigation.</p><p><strong>Conclusion: </strong>LNPs/miR-10a-AMOs can efficiently deliver AMOs and represent a potential strategy for treating CRC. By enhancing the sensitivity of tumors to cisplatin, this system improved the therapeutic effect while ensuring the safety of normal cells. This provides a new strategy with translational potential for the precise treatment of CRC.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Eg5 with K858: A Strategy for Radiosensitization Through ROS-Mediated DNA Damage in Esophageal Squamous Cell Carcinoma.","authors":"Ruixue Liu, Shuo Zhou, Feng Xiao, Mengmeng Chen, Xinchen Xu, Xiaolong Liu","doi":"10.2174/0118715206454040260529233935","DOIUrl":"https://doi.org/10.2174/0118715206454040260529233935","url":null,"abstract":"<p><strong>Introduction: </strong>Radiotherapy resistance poses a major challenge in the treatment of esophageal squamous cell carcinoma (ESCC). The kinesin Eg5 is overexpressed in human cancers and has emerged as a candidate therapeutic target. The Eg5 inhibitor K858 cooperates with radiotherapy to block ESCC progression, but whether this synergy stems from modulation of irradiation-induced reactive oxygen species (ROS) and DNA damage is unknown. We aimed to establish the clinical significance of Eg5 in ESCC, and to investigate whether pharmacological Eg5 inhibition by K858 enhances radiosensitivity via ROS-mediated DNA damage.</p><p><strong>Methods: </strong>We employed bioinformatic interrogation of public databases, retrospective analysis of an institutional patient cohort (n = 30) with immunohistochemistry validation, and in vitro studies using ESCC cell lines. We assessed correlations between Eg5 expression levels, clinicopathological features, and patient survival. ROS generation was measured by flow cytometry, and γH2AX foci detection by immunofluorescence following K858 and radiotherapy treatment.</p><p><strong>Results: </strong>Eg5 mRNA and protein levels were highly upregulated across ESCC and various cancers compared to normal tissues. Eg5 expression correlated with smoking history, poorer histological grade, and reduced overall survival in our patient cohort. Furthermore, a negative correlation between Eg5 expression and E-cadherin status identified Eg5 as a regulator of epithelial-mesenchymal transition. Mechanistically, K858 treatment enhanced ROS generation and increased γH2AX foci accumulation induced by radiotherapy, indicating that inhibition of Eg5 promotes radiotherapy efficacy through oxidative DNA injury.</p><p><strong>Discussion: </strong>These data support the combination of K858, an Eg5-targeting compound, and radiotherapy as a strategy for treating ESCC by enhancing oxidative stress and unresolved DNA lesions. Our results suggest that kinesin Eg5 may be utilized not only as a prognostic biomarker but also as a bona fide target for overcoming radioresistance.</p><p><strong>Conclusion: </strong>Eg5 represents not only an independent prognostic marker but also a promising drug target for ESCC, yet the findings still need to be validated in large-scale prospective studies. Inhibiting this kinesin protein with K858 may represent a novel therapeutic strategy to sensitize ESCC to radiotherapy.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic Anticancer Effect of Luteolin and Etoposide via the PI3K/AKT Signaling Pathway.","authors":"Weilin Huang, Feng Liang, Hui Xu, Rui Zhang, Mingyi Zhao, Ting Sun","doi":"10.2174/0118715206430858260313082444","DOIUrl":"https://doi.org/10.2174/0118715206430858260313082444","url":null,"abstract":"<p><strong>Background: </strong>Etoposide (VP-16) is a widely used chemotherapeutic agent, but its efficacy is limited by toxicity and resistance. Luteolin (LUT), a natural flavonoid, exhibits antitumor activity and may enhance chemotherapy through signaling modulation. This study explores the synergistic effects of LUT and VP-16 and the underlying mechanism.</p><p><strong>Methods: </strong>The H22 and 4T1 mouse tumor cells, as well as the human hepatocellular carcinoma cell line Huh7, were treated with LUT, VP-16, or their combination. The cell viability, colony formation, and apoptosis were evaluated by CCK-8 assay, crystal violet staining, and TUNEL assay, and the synergistic effect was analyzed using the combination index. The involvement of the PI3K/AKT signaling pathway was detected by Western blotting, and the agonist rescue experiment was conducted for verification. Antitumor efficacy and systemic toxicity were further evaluated in a subcutaneous xenograft mouse model.</p><p><strong>Results: </strong>LUT and VP-16 combination significantly inhibited proliferation and clonogenic potential while promoting apoptosis in all tested cell lines (P < 0.01). Western blotting showed suppression of PI3K and AKT phosphorylation, effects reversed by 740 Y-P. In vivo, the combination produced the strongest tumor reduction with enhanced apoptosis and reduced PI3K/AKT activation.</p><p><strong>Discussion: </strong>The synergistic effect of LUT and VP-16 is largely mediated by PI3K/AKT pathway inhibition, providing mechanistic insight into their combined antitumor action and suggesting a strategy to enhance chemotherapy efficacy.</p><p><strong>Conclusion: </strong>LUT enhances the antitumor efficacy of VP-16 by synergistically inhibiting the PI3K/AKT signaling pathway. This combination presents a promising therapeutic strategy for improving chemotherapy outcomes in solid tumors.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}