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

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

Research output: Contribution to journalArticle

313 Citations (Scopus)

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 μM curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-γ1 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 antiapoptotic 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.

Original languageEnglish
Pages (from-to)1199-1208
Number of pages10
JournalCarcinogenesis
Volume24
Issue number7
DOIs
Publication statusPublished - 2003 Jul 1

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Curcumin
Cytochromes c
Reactive Oxygen Species
Down-Regulation
Apoptosis
Caspase Inhibitors
DNA Fragmentation
Caspase 3
bcl-X Protein
Curcuma
Rhizome
Type C Phospholipases
Caspases
Ketones
Cyclosporine
Cysteine
Cell Survival
Cell Death
Anti-Inflammatory Agents
Kidney

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Woo, Ju Hyung ; Kim, Young Ho ; Choi, Yun Jung ; Kim, Dae Gon ; Lee, Kyung Seop ; Bae, Jae Hoon ; Min, Do Sik ; Chang, Jong Soo ; Jeong, Yong Jin ; Lee, Young Han ; Park, Jong Wook ; Kwon, Taeg Kyu. / 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. In: Carcinogenesis. 2003 ; Vol. 24, No. 7. pp. 1199-1208.
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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 μM curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-γ1 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 antiapoptotic 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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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. / Woo, Ju Hyung; Kim, Young Ho; Choi, Yun Jung; Kim, Dae Gon; Lee, Kyung Seop; Bae, Jae Hoon; Min, Do Sik; Chang, Jong Soo; Jeong, Yong Jin; Lee, Young Han; Park, Jong Wook; Kwon, Taeg Kyu.

In: Carcinogenesis, Vol. 24, No. 7, 01.07.2003, p. 1199-1208.

Research output: Contribution to journalArticle

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T1 - Molecular mechanisms of curcumin-induced cytotoxicity

T2 - 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

AU - Woo, Ju Hyung

AU - Kim, Young Ho

AU - Choi, Yun Jung

AU - Kim, Dae Gon

AU - Lee, Kyung Seop

AU - Bae, Jae Hoon

AU - Min, Do Sik

AU - Chang, Jong Soo

AU - Jeong, Yong Jin

AU - Lee, Young Han

AU - Park, Jong Wook

AU - Kwon, Taeg Kyu

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