Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro-survival Akt and mTOR.
BACKGROUND
Synthetic triterpenoids are potent anticancer agents, but their therapeutic efficacy or mechanism of action for prostate cancer has not been investigated. The goal of this study was to determine the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human prostate cancer cells.


METHODS
The antitumor activity of CDDO-Me for hormone-refractory PC-3 (AR(-)) and C4-2 (AR(+)) prostate cancer cell lines was determined by effects on cell growth and induction of apoptosis, identification of molecular targets, and therapeutic efficacy in vivo in PC-3 xenograft model.


RESULTS
CDDO-Me inhibited the growth and induced apoptosis in PC-3 and C4-2 cells at extremely low concentrations. The antitumor activity of CDDO-Me was associated with the inhibition of p-Akt, mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-kappaB) signaling proteins and their downstream targets such as p-Bad and p-Foxo3a (Akt); p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR); and COX-2, VEGF and cyclin D1(NF-kappaB). Silencing of Akt sensitized the PC-3 cells to CDDO-Me, whereas overexpression of Akt induced resistance to CDDO-Me. Targeted silencing of Akt showed that Akt does not regulate mTOR activation in PC-3 cells, but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition. Further, treatment with CDDO-Me inhibited the growth of PC-3 xenografts in nude mice.


CONCLUSIONS
This study demonstrated potent antitumor activity of CDDO-Me against prostate cancer cells both in vitro and in vivo. Data also identified Akt and mTOR as molecular targets of CDDO-Me in prostate cancer cells.
Deeb
Dorrah
D
Departments of Surgery, Henry Ford Health System, One Ford Place, Detroit, MI 48202, USA.
Gao
Xiaohua
X
Jiang
Hao
H
Dulchavsky
Scott A
SA
Gautam
Subhash C
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000187:drug effects / Q000302:isolation & purification; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D011494:Protein Kinases / Q000187:drug effects / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases; D014183:Transplantation, Heterologous; D014315:Triterpenes / Q000494:pharmacology*
D016328:NF-kappa B; D009687:Nuclear Proteins; D014315:Triterpenes; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases