2. Academic Validation
  3. Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

  • Cancers (Basel). 2021 Dec 4;13(23):6117. doi: 10.3390/cancers13236117.
Tsung-Han Hsieh 1 2,  Muh-Lii Liang 3 4,  Jia-Huei Zheng 1,  Yu-Chen Lin 5 6,  Yu-Chen Yang 1,  Thanh-Hoa Vo 7,  Jing-Ping Liou 8,  Yun Yen 9 10,  Chun-Han Chen 5 6 11
Affiliations

Affiliations

  • 1 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 110, Taiwan.
  • 2 Neuroscience Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan.
  • 3 Department of Neurosurgery, Mackay Memorial Hospital, Taipei 104, Taiwan.
  • 4 Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
  • 5 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 6 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 7 School of Medicine, Vietnam National University Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 9 The Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
  • 10 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 11 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
PMID: 34885226 DOI: 10.3390/cancers13236117
Abstract

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 phosphorylation 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.

Keywords

MPT0L145; abemaciclib; glioblastoma multiforme; synergism.

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