Carcinogenesis Advance Access originally published online on May 9, 2003
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Carcinogenesis, Vol. 24, No. 7, 1199-1208,
July 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt
1 Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu, 700-712, South Korea
2 Department of Urology, College of Medicine, Dongguk University, Kyungju, South Korea
3 Department of Physiology School of Medicine, Keimyung University, Taegu, South Korea
4 Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea
5 Department of Life Science, Daejin University, Pochon-gun, Kyeonggido, South Korea
6 Department of Food Science and Technology, Keimyung University, Taegu, South Korea
7 Department of Biochemistry, College of Medicine, Yeungnam University, Taegu, South Korea
8 To whom correspondence should be addressed Email: kwontk{at}dsmc.or.kr
Curcumin, a natural, biologically active compound extracted from rhizomes of Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor and anti-oxidative properties. The mechanism by which curcumin initiates apoptosis remains poorly understood. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human renal Caki cells. Treatment of Caki cells with 50 µM curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-
1 and DNA fragmentation. Curcumin-induced apoptosis is mediated through the activation of caspase, which is specifically inhibited by the caspase inhibitor, benzyloxycarbony-Val-Ala-Asp-fluoromethyl ketone. Curcumin causes dose-dependent apoptosis and DNA fragmentation of Caki cells, which is preceded by the sequential dephosphorylation of Akt, down-regulation of the anti-apoptotic Bcl-2, Bcl-XL and IAP proteins, release of cytochrome c and activation of caspase 3. Cyclosporin A, as well as caspase inhibitor, specifically inhibit curcumin-induced apoptosis in Caki cells. Pre-treatment with N-acetyl-cysteine, markedly prevented dephosphorylation of Akt, and cytochrome c release, and cell death, suggesting a role for reactive oxygen species in this process. The data indicate that curcumin can cause cell damage by inactivating the Akt-related cell survival pathway and release of cytochrome c, providing a new mechanism for curcumin-induced cytotoxicity.
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