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J Urol. 2011 May;185(5):1967-74. doi: 10.1016/j.juro.2010.12.091. Epub 2011 Mar 21.

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

Author information

1
School of Pharmacy, National Taiwan University, Taipei, Taiwan, Republic of China.

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 Ca(2+), 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 Ca(2+) chelator BAPTA-AM other than the reactive oxygen species scavenger Trolox®. This indicated the crucial role of intracellular Ca(2+) 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 Ca(2+) 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.

PMID:
21421237
DOI:
10.1016/j.juro.2010.12.091
[Indexed for MEDLINE]

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