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Oleanane Triterpenoid CDDO‐Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro‐survival Akt and mTOR
Author(s) -
Deeb Dorrah,
Gao Xiaohua,
Jiang Hao,
Dulchavsky Scott A.,
Gautam Subhash C.
Publication year - 2009
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20937
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , cancer research , apoptosis , prostate cancer , cell growth , chemistry , pten , gene silencing , rptor , medicine , cancer , biochemistry , gene
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‐κB) 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‐κB). 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. Prostate 69: 851–860, 2009. © 2009 Wiley‐Liss, Inc.