Roh Tae Hoon, Lee Ji-Hyun, Kim Seo Jin, Shim Jin-Kyoung, Park Junseong, Yoon Seon-Jin, Teo Wan-Yee, Kim Se Hoon, Chang Jong Hee, Kang Seok-Gu
Department of Neurosurgery, Brain Tumor Center, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea.
Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
J Neurooncol. 2022 Jan;156(1):139-151. doi: 10.1007/s11060-021-03903-7. Epub 2021 Nov 22.
Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs).
The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model.
IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test).
IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.
胶质母细胞瘤（GBM）是中枢神经系统中一种代谢改变的快速生长肿瘤。有人提出用双胍类药物消耗肿瘤的生物能量是治疗GBM的一种有效治疗方法。本研究的目的是确定一种具有改善药代动力学的新型双胍类药物IM1761065对GBM肿瘤球（TSs）的影响。
检测IM1761065对GBM-TSs的生物学活性，包括其对活力、ATP水平、细胞周期、干性、侵袭特性和转录组的影响。在小鼠原位异种移植模型中测试IM1761065的体内疗效。
IM1761065以剂量依赖性方式降低GBM-TSs的活力和ATP水平，并降低患者来源的GBM-TS中基础和备用呼吸能力，通过耗氧率测量。IM1761065还显著抑制了GBM-TSs的球体形成、干性相关蛋白的表达和侵袭能力。对IM1761065处理组的基因本体比较显示，IM1761065也显著下调了干性相关、上皮间质转化相关和线粒体复合体I基因的表达水平。原位异种移植小鼠模型显示，在第5周时，注射IM1761065处理细胞的小鼠体内生物发光降低。IM1761065处理组的生存期比对照组更长（P = 0.0289，对数秩检验）。
IM1761065是氧化磷酸化的有效抑制剂。IM1761065对GBM-TS生物能量的抑制作用表明，这种新型化合物可作为治疗GBM的新药。
