JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wu, H.-Y.
Right arrow Articles by Kang, Y. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wu, H.-Y.
Right arrow Articles by Kang, Y. J.

Vol. 287, Issue 2, 515-520, November 1998

Inhibition of Buthionine Sulfoximine-Enhanced Doxorubicin Toxicity in Metallothionein Overexpressing Transgenic Mouse Heart1

Hui-Yun Wu and Y. James Kang

Departments of Medicine, and Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky

Cardiotoxicity and acquired drug resistance of tumor cells have been two impediments for the clinical use of doxorubicin (DOX). Trials are ongoing using buthionine sulfoximine (BSO) to deplete glutathione (GSH) content in tumors, whose elevation was found to contribute to the acquired drug resistance. However, BSO also decreases GSH content in the heart, enhancing DOX cardiotoxicity. Recent studies have shown that metallothionein (MT) is an important factor in cardiac protection against DOX. Our study was undertaken to determine whether MT can compensate for the loss of protection from GSH depletion in the heart. Transgenic mice with cardiac MT concentrations about 20-fold higher than normal, and nontransgenic controls were treated with BSO by i.p. injection at 5 mmol/kg, two times with a 12-hr interval, before treatment with DOX at a single dose of 15 mg/kg, lasting for 4 days. Cardiac GSH was depleted by 60% in both transgenic and non-transgenic mice. DOXinduced cardiotoxicity, as measured by blood levels of creatine kinase and malondialdehyde concentrations in the heart, was dramatically increased in the BSO-treated nontransgenic mice. This increase was completely inhibited in the BSO-treated transgenic mice. These results demonstrate that cardiac MT overexpressing transgenic mice are resistant to BSO-enhanced DOX cardiotoxicity. Selective modulations of decreasing DOX resistance in tumors by BSO and of increasing cardioprotection by MT induction may provide an alternative approach to improved DOX chemotherapeutic efficacy.

0022-3565/98/2872-0515$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Eur J Heart FailHome page
X. Wang, J. Zhang, and T. Xu
Cyclophosphamide-evoked heart failure involves pronounced co-suppression of cytoplasmic thioredoxin reductase activity and non-protein free thiol level
Eur J Heart Fail, February 1, 2009; 11(2): 154 - 162.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
K. E. Merten, Y. Jiang, and Y. J. Kang
Zinc Inhibits Doxorubicin-Activated Calcineurin Signal Transduction Pathway in H9c2 Embryonic Rat Cardiac Cells
Experimental Biology and Medicine, May 1, 2007; 232(5): 682 - 689.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
L. Cai, Y. Wang, G. Zhou, T. Chen, Y. Song, X. Li, and Y. J. Kang
Attenuation by Metallothionein of Early Cardiac Cell Death via Suppression of Mitochondrial Oxidative Stress Results in a Prevention of Diabetic Cardiomyopathy
J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1688 - 1697.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
X. Sun and Y. J. Kang
Prior Increase in Metallothionein Levels Is Required to Prevent Doxorubicin Cardiotoxicity
Experimental Biology and Medicine, September 1, 2002; 227(8): 652 - 657.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
Z. Zhou, X. Sun, J. C. Lambert, J. T. Saari, and Y. J. Kang
Metallothionein-Independent Zinc Protection from Alcoholic Liver Injury
Am. J. Pathol., June 1, 2002; 160(6): 2267 - 2274.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. McHowat, L. M. Swift, A. Arutunyan, and N. Sarvazyan
Clinical Concentrations of Doxorubicin Inhibit Activity of Myocardial Membrane-associated, Calcium-independent Phospholipase A2
Cancer Res., May 1, 2001; 61(10): 4024 - 4029.
[Abstract] [Full Text]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G.-W. Wang, Z. Zhou, J. B. Klein, and Y. J. Kang
Inhibition of hypoxia/reoxygenation-induced apoptosis in metallothionein-overexpressing cardiomyocytes
Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2292 - H2299.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
X. Sun, Z. Zhou, and Y. J. Kang
Attenuation of Doxorubicin Chronic Toxicity in Metallothionein-overexpressing Transgenic Mouse Heart
Cancer Res., April 1, 2001; 61(8): 3382 - 3387.
[Abstract] [Full Text]

Home page
 Am. J. Pathol.Home page
Z. Zhou and Y. J. Kang
Immunocytochemical Localization of Metallothionein and its Relation to Doxorubicin Toxicity in Transgenic Mouse Heart
Am. J. Pathol., May 1, 2000; 156(5): 1653 - 1662.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
Y. J. Kang
The Antioxidant Function of Metallothionein in the Heart
Experimental Biology and Medicine, December 1, 1999; 222(3): 263 - 273.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.