Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
Neuro Oncol. 2018 Jun 18;20(7):954-965. doi: 10.1093/neuonc/nox243.
Targeted approaches for treating glioblastoma (GBM) attempted to date have consistently failed, highlighting the imperative for treatment strategies that operate on different mechanistic principles. Bioenergetics deprivation has emerged as an effective therapeutic approach for various tumors. We have previously found that cancer cells preferentially utilize cytosolic NADH supplied by aldehyde dehydrogenase (ALDH) for ATP production through oxidative phosphorylation (OxPhos). This study is aimed at examining therapeutic responses and underlying mechanisms of dual inhibition of ALDH and OxPhos against GBM.
For inhibition of ALDH and OxPhos, the corresponding inhibitors, gossypol and phenformin were used. Biological functions, including ATP levels, stemness, invasiveness, and viability, were evaluated in GBM tumorspheres (TSs). Gene expression profiles were analyzed using microarray data. In vivo anticancer efficacy was examined in a mouse orthotopic xenograft model.
Combined treatment of GBM TSs with gossypol and phenformin significantly reduced ATP levels, stemness, invasiveness, and cell viability. Consistently, this therapy substantially decreased expression of genes associated with stemness, mesenchymal transition, and invasion in GBM TSs. Supplementation of ATP using malate abrogated these effects, whereas knockdown of ALDH1L1 mimicked them, suggesting that disruption of ALDH-mediated ATP production is a key mechanism of this therapeutic combination. In vivo efficacy confirmed remarkable therapeutic responses to combined treatment with gossypol and phenformin.
Our findings suggest that dual inhibition of tumor bioenergetics is a novel and effective strategy for the treatment of GBM.
迄今为止，针对胶质母细胞瘤（GBM）的靶向治疗方法一直未能取得成功，这凸显了迫切需要采用不同作用机制的治疗策略。生物能量剥夺已成为治疗各种肿瘤的有效方法。我们之前发现，癌细胞通过氧化磷酸化（OxPhos）优先利用醛脱氢酶（ALDH）供应的细胞质 NADH 来产生 ATP。本研究旨在研究双重抑制 ALDH 和 OxPhos 对 GBM 的治疗反应和潜在机制。
使用相应的抑制剂，即棉酚和苯乙双胍，来抑制 ALDH 和 OxPhos。在 GBM 肿瘤球体（TSs）中评估包括 ATP 水平、干性、侵袭性和活力在内的生物学功能。使用微阵列数据分析基因表达谱。在小鼠原位异种移植模型中检查体内抗癌疗效。
棉酚和苯乙双胍联合治疗 GBM TSs 可显著降低 ATP 水平、干性、侵袭性和细胞活力。一致地，这种治疗方法大大降低了 GBM TSs 中与干性、间质转化和侵袭相关的基因表达。使用苹果酸补充 ATP 可消除这些作用，而敲低 ALDH1L1 则模拟了这些作用，表明破坏 ALDH 介导的 ATP 产生是该治疗组合的关键机制。体内疗效证实了棉酚和苯乙双胍联合治疗的显著治疗反应。
我们的研究结果表明，双重抑制肿瘤生物能量是治疗 GBM 的一种新的有效策略。
