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

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 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 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.

Original languageEnglish
Pages (from-to)1967-1974
Number of pages8
JournalJournal of Urology
Volume185
Issue number5
DOIs
Publication statusPublished - May 2011
Externally publishedYes

Fingerprint

DNA Damage
Prostatic Neoplasms
Apoptosis
Cyclin-Dependent Kinase 2
G1 Phase Cell Cycle Checkpoints
Reactive Oxygen Species
Cyclin E
Phosphorylation
lissamine rhodamine B
Sulfhydryl Compounds
Glutathione
Up-Regulation
Sesquiterpenes
Acetylcysteine
G1 Phase
Lactones
Chelating Agents
costunolide
Androgens
Esters

Keywords

  • calcium
  • costunolide
  • DNA damage
  • prostate
  • prostatic neoplasms

ASJC Scopus subject areas

  • Urology

Cite this

Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer. / Hsu, Jui Ling; Pan, Shiow Lin; Ho, Yunn Fang; Hwang, Tsong Long; Kung, Fan Lu; Guh, Jih Hwa.

In: Journal of Urology, Vol. 185, No. 5, 05.2011, p. 1967-1974.

Research output: Contribution to journalArticle

Hsu, Jui Ling ; Pan, Shiow Lin ; Ho, Yunn Fang ; Hwang, Tsong Long ; Kung, Fan Lu ; Guh, Jih Hwa. / Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer. In: Journal of Urology. 2011 ; Vol. 185, No. 5. pp. 1967-1974.
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AB - 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 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 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.

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