國家衛生研究院 NHRI:Item 3990099045/5595

NHRI > Institute of Biotechnology and Pharmaceutical Research > Shiow-Lin Pan(2009-2013) > Periodical Articles > Item 3990099045/5595

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/5595

Title:	Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer
Authors:	Hsu, JL;Pan, SL;Ho, YF;Hwang, TL;Kung, FL;Guh, JH
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	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.
Date:	2011-05
Relation:	Journal of Urology. 2011 May;185(5):1967-1974.
Link to:	http://dx.doi.org/10.1016/j.juro.2010.12.091
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-5347&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000289279600131
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=79953799722
Appears in Collections:	[Shiow-Lin Pan(2009-2013)] Periodical Articles

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