Combining an autophagy inhibitor, mpt0l145, with abemaciclib is a new therapeutic strategy in gbm treatment

Tsung Han Hsieh, Muh Lii Liang, Jia Huei Zheng, Yu Chen Lin, Yu Chen S.H. Yang, Thanh Hoa Vo, Jing Ping Liou, Yun Yen, Chun Han Chen

研究成果: 雜誌貢獻文章同行評審

1 引文 斯高帕斯(Scopus)

摘要

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phos-phorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future.

原文英語
文章編號6117
期刊Cancers
13
發行號23
DOIs
出版狀態已發佈 - 12月 1 2021

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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