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J. Biol. Chem., Vol. 282, Issue 37, 26759-26766, September 14, 2007

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Chronic Treatment with Resveratrol Induces Redox Stress- and Ataxia Telangiectasia-mutated (ATM)-dependent Senescence in p53-positive Cancer Cells^*

From the Department of Pharmacognosy, University of Vienna, Vienna 1090 Austria

The induction of senescence, an irreversible growth arrest, in cancer cells is regarded as a mean to halt tumor progression. The phytoalexin resveratrol (RV) is known to possess a variety of cancer-preventive, -therapeutic, and -chemosensitizing properties. We report here that chronic treatment with RV in a subapoptotic concentration induces senescence-like growth arrest in tumor cells. In contrast to the widely accepted antioxidant property of RV, we demonstrate that one causative stimulus for senescence induction by chronic RV is an increased level of reactive oxygen species (ROS). The ROS formed upon RV exposure include hydrogen peroxide and superoxide and originate largely from mitochondria. Consistently, co-incubation with the antioxidant N-acetyl cysteine interfered with RV-mediated reactivation of the senescence program. Molecular mediators on the way from increased ROS levels to the observed growth arrest include p38 MAPK, p53, and p21. Moreover, we provide evidence that RV-initiated replication stress, apparent by activation of the ataxia telangiectasia-mutated kinase pathway, is associated with increased ROS levels and senescence induction. This is the first report linking cell cycle effects with a pro-oxidant and pro-senescent effect of RV in cancer cells.

Received for publication, April 17, 2007 , and in revised form, June 20, 2007.

Addendum—During the preparation of this manuscript, Boocock et al. (49) published the results of a phase I dose escalation pharmacokinetic study with RV in healthy volunteers. Examining blood and urine after oral incorporation of RV, they found up to eight times higher systemic levels of RV metabolites (sulfate and monoglucuronides) than of the parent compound. These findings warrant the investigation of the pharmacological profile of RV metabolites. Moreover, and as for almost all chemotherapeutic agents, a selective targeting of RV to cancer cells seems desirable since a pro-oxidative and/or pro-senescent effect in untransformed cells cannot be excluded at this point.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and four supplemental figures.

¹ To whom correspondence should be addressed: Dept. of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Tel.: 43-1-4277-55993; Fax: 43-1-4277-55969; E-mail: elke.heiss{at}univie.ac.at.

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				S. A. Gatz and L. Wiesmuller Take a break--resveratrol in action on DNA Carcinogenesis, February 1, 2008; 29(2): 321 - 332. [Abstract] [Full Text] [PDF]