Mitochondrial dysfunction contributes to Rapamycin-induced apoptosis of Human Glioblastoma Cells - A synergistic effect with Temozolomide

Mammalian target of rapamycin (mTOR) is upregulated in a high percentage of glioblastomas. While a well-known mTOR inhibitor, rapamycin, has been shown to reduce glioblastoma survival, the role of mitochondria in achieving this therapeutic effect is less well known. Here, we examined mitochondrial d...

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Bibliographic Details
Published in:International journal of medical sciences 2020-01, Vol.17 (17), p.2831-2843
Main Authors: Zimmerman, Mary A, Wilkison, Samantha, Qi, Qi, Chen, Guisheng, Li, P. Andy
Format: Article
Language:English
Subjects:
Angiogenesis
Apoptosis
Autophagy
Brain cancer
Cancer therapies
Hypoxia
Kinases
Medical prognosis
Membranes
Mitochondria
Mutation
Proteins
Research Paper
Signal transduction
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Summary:Mammalian target of rapamycin (mTOR) is upregulated in a high percentage of glioblastomas. While a well-known mTOR inhibitor, rapamycin, has been shown to reduce glioblastoma survival, the role of mitochondria in achieving this therapeutic effect is less well known. Here, we examined mitochondrial dysfunction mechanisms that occur with the suppression of mTOR signaling. We found that, along with increased apoptosis, and a reduction in transformative potential, rapamycin treatment significantly affected mitochondrial health. Specifically, increased production of reactive oxygen species (ROS), depolarization of the mitochondrial membrane potential (MMP), and altered mitochondrial dynamics were observed. Furthermore, we verified the therapeutic potential of rapamycin-induced mitochondrial dysfunction through co-treatment with temzolomide (TMZ), the current standard of care for glioblastoma. Together these results demonstrate that the mitochondria remain a promising target for therapeutic intervention against human glioblastoma and that TMZ and rapamycin have a synergistic effect in suppressing glioblastoma viability, enhancing ROS production, and depolarizing MMP.
ISSN:1449-1907
1449-1907
DOI:10.7150/ijms.40159