Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells

Claudia R Oliva; Tahireh Markert; Larry J Ross; E Lucile White; Lynn Rasmussen; Wei Zhang; Maaike Everts; Douglas R Moellering; Shannon M Bailey; Mark J Suto; Corinne E Griguer

doi:10.1074/jbc.M116.749978

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Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells

Journal article

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Peer reviewed

Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells

Claudia R Oliva, Tahireh Markert, Larry J Ross, E Lucile White, Lynn Rasmussen, Wei Zhang, Maaike Everts, Douglas R Moellering, Shannon M Bailey, Mark J Suto, …

The Journal of biological chemistry, Vol.291(46), pp.24188-24199

11/11/2016

DOI: 10.1074/jbc.M116.749978

PMCID: PMC5104942

PMID: 27679486

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Abstract

The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.1) is a large transmembrane protein complex that serves as the last enzyme in the respiratory electron transport chain of eukaryotic mitochondria. CcO promotes the switch from glycolytic to oxidative phosphorylation (OXPHOS) metabolism and has been associated with increased self-renewal characteristics in gliomas. Increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure, and patients with primary glioblastoma multiforme and high tumor CcO activity have worse clinical outcomes than those with low tumor CcO activity. Therefore, CcO is an attractive target for cancer therapy. We report here the characterization of a CcO inhibitor (ADDA 5) that was identified using a high throughput screening paradigm. ADDA 5 demonstrated specificity for CcO, with no inhibition of other mitochondrial complexes or other relevant enzymes, and biochemical characterization showed that this compound is a non-competitive inhibitor of cytochrome c When tested in cellular assays, ADDA 5 dose-dependently inhibited the proliferation of chemosensitive and chemoresistant glioma cells but did not display toxicity against non-cancer cells. Furthermore, treatment with ADDA 5 led to significant inhibition of tumor growth in flank xenograft mouse models. Importantly, ADDA 5 inhibited CcO activity and blocked cell proliferation and neurosphere formation in cultures of glioma stem cells, the cells implicated in tumor recurrence and resistance to therapy in patients with glioblastoma. In summary, we have identified ADDA 5 as a lead CcO inhibitor for further optimization as a novel approach for the treatment of glioblastoma and related cancers.

Electron Transport Complex IV - antagonists & inhibitors

Glioma - enzymology

Cytochromes c - metabolism

Humans

Enzyme Inhibitors - pharmacology

Neoplasm Proteins - antagonists & inhibitors

Neoplasm Proteins - metabolism

Electron Transport Complex IV - metabolism

Xenograft Model Antitumor Assays

Animals

Cell Line, Tumor

Mice

Glioma - drug therapy

Drug Resistance, Neoplasm - drug effects

Details

Title: Subtitle: Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells
Creators: Claudia R Oliva - From the Department of Neurosurgery
Tahireh Markert - From the Department of Neurosurgery
Larry J Ross - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205
E Lucile White - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205
Lynn Rasmussen - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205
Wei Zhang - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205
Maaike Everts - Department of Pediatrics, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama 35294
Douglas R Moellering - UAB Nutrition Sciences Department, Diabetes Research Center BARB Core, University of Alabama at Birmingham, Birmingham, Alabama 35294
Shannon M Bailey - Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, and
Mark J Suto - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205
Corinne E Griguer - Center for Free Radical Biology, and
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.291(46), pp.24188-24199
DOI: 10.1074/jbc.M116.749978
PMID: 27679486
PMCID: PMC5104942
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: UL1 TR001417 / NCATS NIH HHS P30 DK079626 / NIDDK NIH HHS UL1 TR000165 / NCATS NIH HHS R01 CA160821 / NCI NIH HHS
Language: English
Date published: 11/11/2016
Academic Unit: Radiation Oncology; Physical Therapy and Rehabilitation Science
Record Identifier: 9984047639002771

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