ReferenceID 3461
Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer
J Urol
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
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Record Fields
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- Reference Id
- 3461
- Evidence Id
- 20051
- Core Evidence Id
- 20051
- Source Reference Id
- 228
- Herb2 Reference Id
- HBREF000432
- Subject Paper Key
- HBIN021599_21421237
- Pubmed Id
- 21421237
- Doi
- 10.1016/j.juro.2010.12.091
- Paper Title
- Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer
- Paper 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.
- Journal
- J Urol
- Publish Year
- 2011
- Experiment Subject
- human prostate cancer cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer
- Bilingual Status
- semi_complete