Faculty Collaboration Database

Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms. intermediacy of H(2)O(2)- and p53-dependent pathways. J Biol Chem 2004 Jun 11;279(24):25535-43

Date

04/01/2004

Pubmed ID

15054096

DOI

10.1074/jbc.M400944200

Scopus ID

2-s2.0-2942616456 (requires institutional sign-in at Scopus site)   508 Citations

Abstract

Doxorubicin (DOX), a widely used chemotherapeutic agent, exhibits cardiotoxicity as an adverse side effect in cancer patients. DOX-mediated cardiomyopathy is linked to its ability to induce apoptosis in endothelial cells and cardiomyocytes by activation of p53 protein and reactive oxygen species. We evaluated the potential roles of H(2)O(2) and p53 in DOX-induced apoptosis in normal bovine aortic endothelial cells and adult rat cardiomyocytes and in tumor cell lines PA-1 (human ovarian teratocarcinoma) and MCF-7 (human breast adenocarcinoma). Time course measurements indicated that activation of caspase-3 preceded the stimulation of p53 transcriptional activity in endothelial cells. In contrast, DOX caused early activation of p53 in tumor cells that was followed by caspase-3 activation and DNA fragmentation. These findings suggest that the transcriptional activation of p53 in DOX-induced apoptosis in endothelial cells may not be as crucial as it is in tumor cells. Further evidence was obtained using a p53 inhibitor, pifithrin-alpha. Pifithrin-alpha completely suppressed DOX-induced activation of p53 in both normal and tumor cell lines and prevented apoptosis in tumor cell lines but not in endothelial cells and cardiomyocytes. In contrast, detoxification of H(2)O(2), either by redox-active metalloporphyrin or overexpression of glutathione peroxidase, decreased DOX-induced apoptosis in endothelial cells and cardiomyocytes but not in tumor cells. This newly discovered mechanistic difference in DOX-induced apoptotic cell death in normal versus tumor cells will be useful in developing drugs that selectively mitigate the toxic side effects of DOX without affecting its antitumor action.

Author List

Wang S, Konorev EA, Kotamraju S, Joseph J, Kalivendi S, Kalyanaraman B

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

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

Animals
Antibiotics, Antineoplastic
Antioxidants
Apoptosis
Caspase 3
Caspases
Cattle
Cells, Cultured
Doxorubicin
Enzyme Activation
Glutathione Peroxidase
Hydrogen Peroxide
Male
Metalloporphyrins
Rats
Rats, Sprague-Dawley
Tumor Suppressor Protein p53