Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit

Claudia R Oliva; Wei Zhang; Cathy Langford; Mark J Suto; Corinne E Griguer

doi:10.18632/oncotarget.17247

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Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit

Journal article

Open access

Peer reviewed

Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit

Claudia R Oliva, Wei Zhang, Cathy Langford, Mark J Suto and Corinne E Griguer

Oncotarget, Vol.8(23), pp.37568-37583

06/06/2017

DOI: 10.18632/oncotarget.17247

PMCID: PMC5514931

PMID: 28455961

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https://doi.org/10.18632/oncotarget.17247View

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Abstract

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.

Electron Transport Complex IV - antagonists & inhibitors

Mitochondria, Heart - metabolism

Humans

Antineoplastic Agents, Alkylating - pharmacology

Chlorpromazine - pharmacology

Drug Repositioning

Mitochondria, Heart - drug effects

Brain Neoplasms - drug therapy

Brain Neoplasms - metabolism

Electron Transport Complex IV - metabolism

Glioma - metabolism

Xenograft Model Antitumor Assays

Animals

Cattle

Dacarbazine - pharmacology

Dopamine Antagonists - pharmacology

Mice, Nude

Dacarbazine - analogs & derivatives

Cell Line, Tumor

Cell Proliferation - drug effects

Antipsychotic Agents - pharmacology

Glioma - drug therapy

Drug Resistance, Neoplasm - drug effects

Details

Title: Subtitle: Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit
Creators: Claudia R Oliva - Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, 35294 Alabama, USA
Wei Zhang - Southern Research, Birmingham, 35294 Alabama, USA
Cathy Langford - Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, 35294 Alabama, USA
Mark J Suto - Southern Research, Birmingham, 35294 Alabama, USA
Corinne E Griguer - Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, 35294 Alabama, USA
Resource Type: Journal article
Publication Details: Oncotarget, Vol.8(23), pp.37568-37583
DOI: 10.18632/oncotarget.17247
PMID: 28455961
PMCID: PMC5514931
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: United States
Grant note: P20 CA151129 / NCI NIH HHS R01 CA160821 / NCI NIH HHS R01 CA127716 / NCI NIH HHS
Language: English
Date published: 06/06/2017
Academic Unit: Radiation Oncology
Record Identifier: 9984047977402771

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