Faculty Collaboration Database

Mitochondria-targeted antioxidant and glycolysis inhibition: synergistic therapy in hepatocellular carcinoma. Anticancer Drugs 2013 Oct;24(9):881-8

Date

07/23/2013

Pubmed ID

23872912

Pubmed Central ID

PMC4028966

DOI

10.1097/CAD.0b013e32836442c6

Scopus ID

2-s2.0-84883451405 (requires institutional sign-in at Scopus site)   27 Citations

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Mito-carboxy proxyl (Mito-CP), a lipophilic cationic nitroxide, accumulates in the mitochondria because of the large negative transmembrane potential. Studies have shown that these agents act by disrupting the energy-producing mechanism, inducing mitochondrial-mediated apoptosis, and also enhancing the action of other chemotherapeutic agents in cancer cells. We hypothesized that the combination of Mito-CP and glycolysis inhibitor, 2-deoxyglucose (2-DG), would synergistically inhibit HCC in vitro. HepG2 cells and primary hepatocytes were treated with various combinations of Mito-CP and 2-DG. Cell cytotoxicity was measured using the methylthiazolyldiphenyl-tetrazolium bromide assay and ATP bioluminescence assay. In addition, caspase 3/7 enzymatic activity was examined after treatment. Mito-CP and 2-DG induced synergistic cytotoxicity in HepG2 cells in a dose-dependent and time-dependent manner, whereas primary cells remained viable and unaffected after treatment. The intracellular ATP levels of HepG2 cells were suppressed within 6 h of combination treatment, whereas primary cells maintained higher levels of ATP. Dose-dependent increases in caspase 3/7 activity occurred in HepG2 cells in a time-dependent manner, showing the initiation of cell death through the apoptotic pathway. These findings indicate that a combination of Mito-CP and 2-DG effectively inhibits HCC growth in vitro. The increase in caspase 3/7 activity supports the occurrence of 2-DG-induced and Mito-CP-induced apoptotic death in HCC. The inability of the compounds to induce cytotoxicity or suppress the production of ATP in primary hepatocytes provides a selective and synergistic approach for the treatment of HCC.

Author List

Dilip A, Cheng G, Joseph J, Kunnimalaiyaan S, Kalyanaraman B, Kunnimalaiyaan M, Gamblin TC

Authors

Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
Thomas Clark Gamblin MD Professor in the Surgery department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

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

Adenosine Triphosphate
Antineoplastic Agents
Antioxidants
Apoptosis
Carcinoma, Hepatocellular
Cell Survival
Cells, Cultured
Cyclic N-Oxides
Deoxyglucose
Drug Synergism
Enzyme Inhibitors
Glycolysis
Hep G2 Cells
Humans
Kinetics
Liver
Liver Neoplasms
Mitochondria, Liver
Molecular Targeted Therapy
Neoplasm Proteins
Organophosphorus Compounds