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Open AccessArticle

Major Contribution of Caspase-9 to Honokiol-Induced Apoptotic Insults to Human Drug-Resistant Glioblastoma Cells

by Gong-Jhe Wu 1,2, Sun-Ta Yang 2,3 and Ruei-Ming Chen 2,4,5,*
1
Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
2
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3
Department of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, New Taipei City 235, Taiwan
4
TMU Research Center of Cancer Translational Medicine, Taipei 110, Taiwan
5
Anesthesiology and Health Policy Research Center, Taipei Medical University, Taipei 110, Taiwan
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(6), 1450; https://doi.org/10.3390/molecules25061450
Received: 5 October 2019 / Revised: 12 December 2019 / Accepted: 20 March 2020 / Published: 23 March 2020
(This article belongs to the Section Natural Products Chemistry)
Temozolomide (TMZ)-induced chemoresistance to human glioblastomas is a critical challenge now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), can kill human glioblastoma cells and suppresses glioblastoma growth. This study was further aimed to evaluate the effects of honokiol on human drug-resistant glioblastoma cells and the possible mechanisms. The results by data mining in the cancer genome atlas (TCGA) database and immunohistochemistry displayed that expression of caspase-9 mRNA and protein in human glioblastomas was induced. Human TMZ-resistant U87-MG-R9 glioblastoma cells were selected and prepared from human drug-sensitive U87-MG cells. Compared to human drug-sensitive U87-MG cells, TMZ did not affect viability of U87-MG-R9 glioblastoma cells. Interestingly, treatment with honokiol suppressed proliferation and survival of human drug-resistant glioblastoma cells in concentration- and time-dependent manners. Compared to caspase-8 activation, honokiol chiefly increased activity of caspase-9 in U87-MG-R9 cells. Successively, levels of cleaved caspase-3 and activities of caspase-3 and caspase-6 in human TMZ-tolerant glioblastoma cells were augmented following honokiol administration. In parallel, honokiol triggered DNA fragmentation of U87-MG-R9 cells. Accordingly, treatment of human TMZ-resistant glioblastoma cells with honokiol induced cell apoptosis but did not affect cell necrosis. Fascinatingly, suppressing caspase-9 activity using its specific inhibitors repressed honokiol-induced caspase-6 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the major roles of caspase-9 in transducing honokiol-induced mitochondria-dependent apoptosis in human drug-resistant glioblastoma cells. Thus, honokiol may be clinically applied as a drug candidate for treatment of glioblastoma patients with chemoresistance. View Full-Text
Keywords: drug-resistant glioblastomas; honokiol; caspase-9; apoptotic insults drug-resistant glioblastomas; honokiol; caspase-9; apoptotic insults
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Wu, G.-J.; Yang, S.-T.; Chen, R.-M. Major Contribution of Caspase-9 to Honokiol-Induced Apoptotic Insults to Human Drug-Resistant Glioblastoma Cells. Molecules 2020, 25, 1450.

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