Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism

Dorrah Deeb, Xiaohua Gao, Hao Jiang, Branislava Janic, Ali Syed Arbab, Yon Rojanasakul, Scott A. Dulchavsky, Subhash C. Gautam

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

CDDO-Me, a synthetic triterpenoid derived from oleanolic acid, is a promising anticancer agent that has shown strong activity against a wide variety of cancer types in vitro and in vivo. We have previously shown that CDDO-Me induces apoptosis in prostate cancer cells irrespective of their hormonal status. To further understand the proapoptotic mechanism of CDDO-Me, we investigated the role of reactive oxygen species (ROS) in mediating the apoptosis inducing activity of CDDO-Me in LNCaP and PC-3 prostate cancer cell lines. Here, we show that CDDO-Me induces ROS generation from both nonmitochondrial and mitochondrial sources, which is associated with the induction of apoptosis as characterized by increased annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c. In addition, CDDO-Me inhibited cell survival Akt, NF-κB and mTOR signaling proteins. The inhibition of ROS generation by N-acetylcysteine (NAC) or by overexpression of antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase-1 (SOD-1) prevented CDDO-Me-induced apoptosis. Pretreatment with NAC blocked annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c by CDDO-Me. NAC also prevented the inhibition of constitutively active Akt, NF-κB and mTOR by CDDO-Me. Together, these data indicate that ROS plays an essential role in the induction of apoptosis by CDDO-Me in prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)350-360
Number of pages11
JournalBiochemical Pharmacology
Volume79
Issue number3
DOIs
StatePublished - Feb 1 2010
Externally publishedYes

Keywords

  • Apoptosis
  • CCDO-Me
  • Cell survival signaling
  • Mitochondrial depolarization
  • Prostate cancer
  • ROS

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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