Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit
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Claudia R. Oliva1, Wei Zhang2, Cathy Langford1, Mark J. Suto2, Corinne E. Griguer1,3
1Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, 35294 Alabama, USA
2Southern Research, Birmingham, 35294 Alabama, USA
3Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, 35294 Alabama, USA
Corinne E. Griguer, email: [email protected]
Keywords: cytochrome c oxidase, chlorpromazine, glioblastoma, inhibitor, stem cells
Received: December 30, 2016 Accepted: April 07, 2017 Published: April 19, 2017
Patients with glioblastoma have one of the lowest overall survival rates among patients with cancer. Standard of care for patients with glioblastoma includes temozolomide and radiation therapy, yet 30% of patients do not respond to these treatments and nearly all glioblastoma tumors become resistant. Chlorpromazine is a United States Food and Drug Administration-approved phenothiazine widely used as a psychotropic in clinical practice. Recently, experimental evidence revealed the anti-proliferative activity of chlorpromazine against colon and brain tumors. Here, we used chemoresistant patient-derived glioma stem cells and chemoresistant human glioma cell lines to investigate the effects of chlorpromazine against chemoresistant glioma. Chlorpromazine selectively and significantly inhibited proliferation in chemoresistant glioma cells and glioma stem cells. Mechanistically, chlorpromazine inhibited cytochrome c oxidase (CcO, complex IV) activity from chemoresistant but not chemosensitive cells, without affecting other mitochondrial complexes. Notably, our previous studies revealed that the switch to chemoresistance in glioma cells is accompanied by a switch from the expression of CcO subunit 4 isoform 2 (COX4-2) to COX4-1. In this study, chlorpromazine induced cell cycle arrest selectively in glioma cells expressing COX4-1, and computer-simulated docking studies indicated that chlorpromazine binds more tightly to CcO expressing COX4-1 than to CcO expressing COX4-2. In orthotopic mouse brain tumor models, chlorpromazine treatment significantly increased the median overall survival of mice harboring chemoresistant tumors. These data indicate that chlorpromazine selectively inhibits the growth and proliferation of chemoresistant glioma cells expressing COX4-1. The feasibility of repositioning chlorpromazine for selectively treating chemoresistant glioma tumors should be further explored.
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