JCI-20679 suppresses autophagy and enhances temozolomide-mediated growth inhibition of glioblastoma cells
JCI-20679 suppresses autophagy and enhances temozolomide-mediated growth inhibition of glioblastoma cells
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DOI：
10.1016/j.bbrc.2021.12.113
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发表时间：
2022-01-06
影响因子：
3.1
通讯作者：
Nakata, Susumu
中科院分区：
文献类型：
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作者：
Ando, Shota;Moyama, Chiami;Nakata, Susumu
胶质母细胞瘤是脑癌的一种，是最具侵袭性和致命性的恶性肿瘤之一。本研究表明，JCI-20679（一种最初合成的线粒体复合物 I 抑制剂）可增强临床使用的化疗药物替莫唑胺的次优浓度对胶质母细胞瘤细胞的抗增殖作用。使用等效线图和组合指数方法分析替莫唑胺与 JCI-20679 联合的效果，表明该组合在小鼠和人胶质母细胞瘤细胞中具有协同作用。我们发现 JCI-20679 抑制替莫唑胺介导的自噬诱导，从而促进细胞存活。替莫唑胺诱导的自噬增加了 ATP 的产生，从而赋予胶质母细胞瘤细胞对替莫唑胺的耐药性。 JCI-20679 阻断替莫唑胺介导的 ATP 水平增加并增加 AMP/ATP 比率。此外，JCI-20679 增强了替莫唑胺在胶质母细胞瘤原位移植模型中的治疗效果。这些结果表明 JCI-20679 可能有望成为增强替莫唑胺抗胶质母细胞瘤功效的新型药物。 (c) 2022 Elsevier Inc. 保留所有权利。
Glioblastoma, a type of brain cancer, is one of the most aggressive and lethal types of malignancy. The present study shows that JCI-20679, an originally synthesized mitochondrial complex I inhibitor, enhances the anti-proliferative effects of suboptimal concentrations of the clinically used chemotherapeutic drug temozolomide in glioblastoma cells. Analysis of the effects of temozolomide combined with JCI-20679 using isobologram and combination index methods demonstrated that the combination had synergistic effects in murine and human glioblastoma cells. We found that JCI-20679 inhibited the temozolomide-mediated induction of autophagy that facilitates cellular survival. The autophagy induced by temozolomide increased ATP production, which confers temozolomide resistance in glioblastoma cells. JCI-20679 blocked temozolomide-mediated increases in ATP levels and increased the AMP/ATP ratio. Furthermore, JCI-20679 enhanced the therapeutic effects of temozolomide in an orthotopic transplantation model of glioblastoma. These results indicate that JCI-20679 may be promising as a novel agent for enhancing the efficacy of temozolomide against glioblastoma. (c) 2022 Elsevier Inc. All rights reserved.