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

Biochem Pharmacol. 2010 Feb 1;79(3):350-60. doi: 10.1016/j.bcp.2009.09.006. Epub 2009 Sep 24.

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-kappaB 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-kappaB 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Line, Tumor
  • Growth Inhibitors / chemistry
  • Growth Inhibitors / pharmacology*
  • Growth Inhibitors / therapeutic use
  • Humans
  • Male
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / chemistry
  • Oleanolic Acid / pharmacology
  • Oleanolic Acid / therapeutic use
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Reactive Oxygen Species / metabolism*

Substances

  • Growth Inhibitors
  • Reactive Oxygen Species
  • oleanane
  • Oleanolic Acid
  • methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate