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.

Abstract	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 microM curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-gamma1 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.
Authors	Ju-Hyung Woo, Young-Ho Kim, Yun-Jung Choi, Dae-Gon Kim, Kyung-Seop Lee, Jae Hoon Bae, Do Sik Min, Jong-Soo Chang, Yong-Jin Jeong, Young Han Lee, Jong-Wook Park, Taeg Kyu Kwon
Journal	Carcinogenesis (Carcinogenesis) Vol. 24 Issue 7 Pg. 1199-208 (Jul 2003) ISSN: 0143-3334 [Print] England
PMID	12807727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents BCL2L1 protein, human Cytochrome c Group Enzyme Inhibitors Free Radical Scavengers Inhibitor of Apoptosis Proteins Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 RNA, Messenger Reactive Oxygen Species bcl-2-Associated X Protein bcl-X Protein Poly(ADP-ribose) Polymerases AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Caspases Curcumin
Topics	Antineoplastic Agents (pharmacology) Apoptosis (drug effects) Blotting, Western Carcinoma, Renal Cell (metabolism, pathology) Caspases (metabolism) Curcumin (pharmacology) Cytochrome c Group (metabolism) Down-Regulation Enzyme Activation (drug effects) Enzyme Inhibitors (pharmacology) Free Radical Scavengers (pharmacology) Gene Expression Regulation, Neoplastic Humans Inhibitor of Apoptosis Proteins Kidney Neoplasms (metabolism, pathology) Mitochondria (drug effects) Poly(ADP-ribose) Polymerases (metabolism) Protein Serine-Threonine Kinases Proteins (antagonists & inhibitors, metabolism) Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism) Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism) RNA, Messenger (metabolism) Reactive Oxygen Species Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured bcl-2-Associated X Protein bcl-X Protein

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