Department of Neurosurgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea.
Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.
Molecules. 2021 Jan 8;26(2):282. doi: 10.3390/molecules26020282.
Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action.
具有干细胞样特征的肿瘤常驻细胞诱导药物耐受，促进脑胶质瘤（GBM）的存活。我们之前的研究表明，靶向肿瘤生物能量学的策略为治疗 GBM 提供了一种新的新兴途径。本研究的目的是通过联合使用醛脱氢酶抑制剂棉酚和抑制氧化磷酸化的双胍化合物二甲双胍，增强肿瘤生物能量学的双重抑制与化疗药物替莫唑胺（TMZ）联合治疗，以阻断 GBM 肿瘤球体（TSs）的增殖、干性和侵袭性。与 TMZ 单药治疗和棉酚与二甲双胍的双重治疗相比，棉酚、二甲双胍和 TMZ 的联合治疗可显著降低 ATP 水平、细胞活力、干性和侵袭性。差异表达基因分析显示，与细胞代谢、周期和黏附相关的基因下调，而与程序性细胞死亡、自噬和蛋白质代谢相关的基因上调。因此，TMZ 与肿瘤生物能量学的双重抑制剂联合使用可能通过多种作用机制增强治疗效果，从而为 GBM 提供一种有效的治疗策略。
