Glioblastoma (GBM) is one of the deadliest types of cancer, characterized by a short life expectancy after diagnosis, mostly related to therapy resistance and recurrence. GBM stem-like cells (GSCs) reside within the tumor and contribute to these features; therefore, finding drugs that specifically target such cells holds promise to halt GBM progression. The primary objective of this work is to comprehensively review and discuss the potential of hard drug repurposing to target GSCs. Several studies evaluating drugs showing anti-GSC activity, originally approved for non-cancer indications, were identified. These mainly included antidiabetics (e.g., Metformin, Phenformin, and Sitagliptin), antihypertensives (e.g., Nicardipine, Doxazosin, and Prazosin), antimicrobials (e.g., Pyrvinium pamoate, Flubendazole, and Clofazimine), and central nervous system-acting drugs (e.g., Chlorpromazine, Fluvoxamine, and Disulfiram). Relevant candidates include those that disrupt GSC metabolism, namely impairing mitochondrial function, such as Metformin, Chlorpromazine, and Pyrvinium pamoate. Multiple signaling pathways may be involved, namely the Wnt, PI3K/AKT, and STAT3 pathways, among others. Also significant were those drugs tested in combination, resulting in increased sensitivity to Temozolomide (TMZ), the standard pharmacological treatment available for GBM. Some repurposed agents, such as Disulfiram and Metformin, have already reached clinical testing, although none have yet been incorporated into clinical practice. Importantly, major translational barriers remain, like limited blood–brain barrier penetration and the lack of robust clinical trials. In conclusion, drug repurposing is an affordable and suitable strategy to target GSCs, impairing cell viability, reducing stemness, and enhancing their sensitivity to TMZ, which has potential that should be further explored to improve patients’ clinical outcomes.
胶质母细胞瘤（GBM）是最致命的癌症类型之一，其特点是确诊后预期寿命较短，主要与治疗抵抗和复发相关。GBM干细胞样细胞（GSCs）存在于肿瘤内部，是导致这些特征的关键因素；因此，寻找特异性靶向此类细胞的药物有望阻止GBM进展。本研究的主要目的是全面综述并探讨硬性药物重定位靶向GSCs的潜力。研究识别了多项评估具有抗GSC活性药物的相关研究，这些药物最初获批用于非癌症适应症，主要包括降糖药（如二甲双胍、苯乙双胍和西格列汀）、降压药（如尼卡地平、多沙唑嗪和普萘洛尔）、抗微生物药（如扑蛲灵、氟苯达唑和氯法齐明）以及中枢神经系统药物（如氯丙嗪、氟伏沙明和双硫仑）。其中具有潜力的候选药物包括那些破坏GSC代谢的药物，特别是损害线粒体功能的药物，如二甲双胍、氯丙嗪和扑蛲灵。可能涉及多种信号通路，包括Wnt、PI3K/AKT和STAT3通路等。联合用药测试也显示出重要意义，能增强GSCs对标准治疗药物替莫唑胺（TMZ）的敏感性。部分重定位药物（如双硫仑和二甲双胍）已进入临床试验阶段，但尚未应用于临床实践。值得注意的是，仍存在重大转化障碍，包括血脑屏障穿透性有限和缺乏稳健的临床试验。总之，药物重定位是一种经济可行的靶向GSCs策略，能够抑制细胞活力、降低干细胞特性并增强对TMZ的敏感性，这一潜力值得进一步探索以改善患者的临床预后。
Drug Repurposing for Targeting Cancer Stem-like Cells in Glioblastoma
肿瘤(癌症)患者之家