Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism.
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.
Deeb
Dorrah
D
Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Gao
Xiaohua
X
Jiang
Hao
H
Janic
Branislava
B
Arbab
Ali S
AS
Rojanasakul
Yon
Y
Dulchavsky
Scott A
SA
Gautam
Subhash C
SC
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D006131:Growth Inhibitors; D017382:Reactive Oxygen Species; C413246:oleanane; D009828:Oleanolic Acid; C445068:bardoxolone methyl