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¹ Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky; ² Department of Pathology and Laboratory Medicine Service, William S. Middleton Veterans Memorial Hospital, University of Wisconsin, Madison, Wisconsin; and ³ Faculty of Medical Technology, Mahidol University, Bangkok, Thailand

Requests for reprints: Daret K. St. Clair, Graduate Center for Toxicology, University of Kentucky, 454 Health Sciences Research Building, Lexington, KY 40536. Phone: 859-257-3956; Fax: 859-323-1059. E-mail: dstcl00{at}uky.edu

Cardiomyopathy is a major dose-limiting factor for applications of Adriamycin, a potent chemotherapeutic agent. The present study tested the hypothesis that increased tumor necrosis factor (TNF)- signaling via its receptors protects against Adriamycin-induced cardiac injury. We used mice in which both TNF receptor I and II have been selectively inactivated (DKO) with wild-type mice as controls. Morphometric studies of cardiac tissue following Adriamycin treatment revealed greater ultrastructural damage in cardiomyocyte mitochondria from DKO mice. Biochemical studies of cardiac tissues showed cytochrome c release and the increase in proapoptotic protein levels, suggesting that lack of TNF- receptor I and II exacerbates Adriamycin-induced cardiac injury. The protective role of TNF receptor I and II was directly confirmed in isolated primary cardiomyocytes. Interestingly, following Adriamycin treatment, the levels of Fas decreased in the wild-type mice. In contrast, DKO mice had an increase in Fas levels and its downstream target, mitochondrial truncated Bid. These results suggested that TNF- receptors play a critical role in cardioprotection by suppression of the mitochondrial-mediated associated cell death pathway. [Mol Cancer Ther 2006;5(2):261–9]

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Note: The current address for Y-C. Lien is Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032. The current address for S-M. Lin is Nutritional Science, Chung Hwa College of Medical Technology, 717 Tainan, Taiwan. The current address for Q. Zhao is Department of Biochemistry, Guangzhou Medical College, 510182 Guangzhou, China.

⁴ Unpublished data.

Received 9/27/05; revised 11/ 3/05; accepted 11/22/05.

Commentary

Is p21 an oncogene?

Andrei L. Gartel
Mol. Cancer Ther. 2006 5: 1385-1386. [Full Text] [PDF]