Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer

Jui Ling Hsu, Shiow Lin Pan, Yunn Fang Ho, Tsong Long Hwang, Fan Lu Kung, Jih Hwa Guh

研究成果: 雜誌貢獻文章

37 引文 斯高帕斯(Scopus)

摘要

Purpose: Costunolide is a natural sesquiterpene lactone. We elucidated what to our knowledge is a novel mechanism to highlight its potential in chemotherapy for prostate cancer, particularly androgen refractory prostate cancer. Materials and Methods: Several pharmacological and biochemical assays were used to characterize the apoptotic signaling pathways of costunolide (ChromaDex™) in prostate cancer cells. Results: Costunolide showed effective antiproliferative activity against hormone dependent (LNCaP) and independent (PC-3 and DU-145) prostate cancer cells (ATCC®) by sulforhodamine B assay, clonogenic test and flow cytometric analysis of carboxyfluorescein succinimidyl ester labeling. In PC-3 cells data showed that costunolide induced a rapid overload of nuclear Ca2+, DNA damage response and ATR phosphorylation. Costunolide induced G1-phase cell cycle arrest, which was supported by p21 up-regulation and its association with the cyclin dependent kinase 2/cyclin E complex. The association resulted in inhibition of the complex activity and inhibition of Rb phosphorylation. Costunolide mediated effects were substantially inhibited by glutathione, the reactive oxygen species scavenger and glutathione precursor N-acetylcysteine, and the Ca2+ chelator BAPTA-AM other than the reactive oxygen species scavenger Trolox®. This indicated the crucial role of intracellular Ca2+ mobilization and thiol depletion but not of reactive oxygen species production in apoptotic signaling. Conclusions: Data suggest that costunolide induces the depletion of intracellular thiols and overload of nuclear Ca2+ that cause DNA damage and p21 up-regulation. The association of p21 with the cyclin dependent kinase 2/cyclin E complex blocks cyclin dependent kinase 2 activity and inhibits Rb phosphorylation, leading to G1 arrest of the cell cycle and subsequent apoptotic cell death in human prostate cancer cells.
原文英語
頁(從 - 到)1967-1974
頁數8
期刊Journal of Urology
185
發行號5
DOIs
出版狀態已發佈 - 五月 2011
對外發佈Yes

ASJC Scopus subject areas

  • Urology

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