Faculty Collaboration Database

Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death. BMC Cancer 2013 Jun 13;13:285

Date

06/15/2013

Pubmed ID

23764021

Pubmed Central ID

PMC3686663

DOI

10.1186/1471-2407-13-285

Scopus ID

2-s2.0-84878817212 (requires institutional sign-in at Scopus site)   115 Citations

Abstract

BACKGROUND: Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells.

METHODS: In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed.

RESULTS: Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer.

CONCLUSIONS: We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect.

Author List

Cheng G, Zielonka J, McAllister DM, Mackinnon AC Jr, Joseph J, Dwinell MB, Kalyanaraman B

Authors

Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
Michael B. Dwinell PhD Center Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Breast Neoplasms
Cell Death
Cell Line, Tumor
Chromans
Chromatography, High Pressure Liquid
Energy Metabolism
Female
Humans
Mice
Mitochondria
Vitamin E
Xenograft Model Antitumor Assays