Harnessing Repurposed Drugs to Enhance Temozolomide Efficacy in Glioblastoma

IF 2.5 Q4 ONCOLOGY

Cancer reports Pub Date : 2026-08-05 DOI:10.1002/cnr2.70643

Ali Nakhaei, Atefeh Taghavi, Amir R. Afshari, Farzaneh Davoudi, Elaheh Gheybi, Mohammad Jalili-Nik

{"title":"Harnessing Repurposed Drugs to Enhance Temozolomide Efficacy in Glioblastoma","authors":"Ali Nakhaei, Atefeh Taghavi, Amir R. Afshari, Farzaneh Davoudi, Elaheh Gheybi, Mohammad Jalili-Nik","doi":"10.1002/cnr2.70643","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Glioblastoma (GB) is the most aggressive primary malignant brain tumor in adults and remains associated with poor survival despite surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy. Intrinsic and acquired resistance to TMZ, including MGMT-dependent DNA repair and activation of pro-survival pathways, could decrease treatment efficacy. Drug repurposing offers an attractive strategy to identify agents that may enhance TMZ activity because these drugs already have known pharmacokinetic and safety profiles. This narrative review summarizes the available evidence on repurposed drugs investigated as potential modulators of TMZ response in GB.</p>\n </section>\n \n <section>\n \n <h3> Recent Findings</h3>\n \n <p>A range of repurposed agents, including chloroquine, valproic acid, levetiracetam, metformin, aspirin, amlodipine, atorvastatin, chlorpromazine, melatonin, disulfiram, bortezomib, and verteporfin, have been evaluated in GB models and selected clinical studies. Reported mechanisms include modulation of MGMT expression, autophagy, oxidative stress, apoptosis, DNA-damage responses, cancer stem-cell properties, and signaling pathways such as PI3K/AKT/mTOR, AMPK, EGFR, STAT3, ERK1/2, and NF-κB. Several agents have enhanced TMZ-associated cytotoxicity in cell culture and animal models. However, clinical evidence remains limited, and the results are inconsistent for some drugs. Blood–brain barrier penetration, achievable intratumoral drug exposure, toxicity, treatment scheduling, and molecular heterogeneity of GB remain major translational challenges.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Repurposed drugs may provide useful candidates for improving TMZ-based therapy in GB. However, most evidence remains preclinical, and further studies are needed to clarify blood–brain barrier penetration, optimal dosing, toxicity, predictive biomarkers, and clinical efficacy. Well-designed prospective clinical trials are required before these combinations can be incorporated into routine GB treatment.</p>\n </section>\n </div>","PeriodicalId":9440,"journal":{"name":"Cancer reports","volume":"9 8","pages":""},"PeriodicalIF":2.5000,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13442923/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer reports","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cnr2.70643","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Glioblastoma (GB) is the most aggressive primary malignant brain tumor in adults and remains associated with poor survival despite surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy. Intrinsic and acquired resistance to TMZ, including MGMT-dependent DNA repair and activation of pro-survival pathways, could decrease treatment efficacy. Drug repurposing offers an attractive strategy to identify agents that may enhance TMZ activity because these drugs already have known pharmacokinetic and safety profiles. This narrative review summarizes the available evidence on repurposed drugs investigated as potential modulators of TMZ response in GB.

Recent Findings

A range of repurposed agents, including chloroquine, valproic acid, levetiracetam, metformin, aspirin, amlodipine, atorvastatin, chlorpromazine, melatonin, disulfiram, bortezomib, and verteporfin, have been evaluated in GB models and selected clinical studies. Reported mechanisms include modulation of MGMT expression, autophagy, oxidative stress, apoptosis, DNA-damage responses, cancer stem-cell properties, and signaling pathways such as PI3K/AKT/mTOR, AMPK, EGFR, STAT3, ERK1/2, and NF-κB. Several agents have enhanced TMZ-associated cytotoxicity in cell culture and animal models. However, clinical evidence remains limited, and the results are inconsistent for some drugs. Blood–brain barrier penetration, achievable intratumoral drug exposure, toxicity, treatment scheduling, and molecular heterogeneity of GB remain major translational challenges.

Conclusion

Repurposed drugs may provide useful candidates for improving TMZ-based therapy in GB. However, most evidence remains preclinical, and further studies are needed to clarify blood–brain barrier penetration, optimal dosing, toxicity, predictive biomarkers, and clinical efficacy. Well-designed prospective clinical trials are required before these combinations can be incorporated into routine GB treatment.

查看原文本刊更多论文

利用改良药物增强替莫唑胺治疗胶质母细胞瘤的疗效。

背景：胶质母细胞瘤（GB）是成人最具侵袭性的原发性恶性脑肿瘤，尽管手术切除后再进行放疗和替莫唑胺（TMZ）化疗，但其生存率仍然很低。TMZ的内在和获得性耐药，包括mtmt依赖的DNA修复和促生存途径的激活，可能会降低治疗效果。药物再利用为识别可能增强TMZ活性的药物提供了一种有吸引力的策略，因为这些药物已经具有已知的药代动力学和安全性概况。这篇叙述性的综述总结了现有的证据，重新利用的药物研究作为潜在的调节剂的TMZ反应在GB。最近的发现：一系列重新使用的药物，包括氯喹、丙戊酸、左乙拉西坦、二甲双胍、阿司匹林、氨氯地平、阿托伐他汀、氯丙嗪、褪黑激素、双硫仑、硼替佐米和维替波芬，已经在GB模型和选定的临床研究中进行了评估。已报道的机制包括MGMT表达、自噬、氧化应激、凋亡、dna损伤反应、癌症干细胞特性以及PI3K/AKT/mTOR、AMPK、EGFR、STAT3、ERK1/2和NF-κB等信号通路的调节。在细胞培养和动物模型中，一些药物增强了tmz相关的细胞毒性。然而，临床证据仍然有限，一些药物的结果不一致。血脑屏障穿透、可实现的肿瘤内药物暴露、毒性、治疗计划和GB的分子异质性仍然是主要的转化挑战。结论：重新利用的药物可能为改善以tmz为基础的GB治疗提供有用的候选药物。然而，大多数证据仍停留在临床前，需要进一步的研究来阐明血脑屏障穿透性、最佳剂量、毒性、预测性生物标志物和临床疗效。在将这些组合纳入常规GB治疗之前，需要进行精心设计的前瞻性临床试验。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊