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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.
- Source :
-
The Prostate [Prostate] 2009 Jun 01; Vol. 69 (8), pp. 851-60. - Publication Year :
- 2009
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (. (c) 2009 Wiley-Liss, Inc.)
- Subjects :
- Animals
Blotting, Western
Cell Line, Tumor
Cell Survival drug effects
Gene Expression Regulation, Neoplastic drug effects
Humans
Male
Mice
Mice, Nude
NF-kappa B drug effects
NF-kappa B metabolism
Nuclear Proteins drug effects
Nuclear Proteins isolation & purification
Oleanolic Acid pharmacology
Prostatic Neoplasms drug therapy
Prostatic Neoplasms genetics
Protein Kinases drug effects
Proto-Oncogene Proteins c-akt drug effects
TOR Serine-Threonine Kinases
Transplantation, Heterologous
Apoptosis drug effects
Cell Division drug effects
Oleanolic Acid analogs & derivatives
Prostatic Neoplasms pathology
Protein Kinases genetics
Proto-Oncogene Proteins c-akt genetics
Triterpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0045
- Volume :
- 69
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Prostate
- Publication Type :
- Academic Journal
- Accession number :
- 19189297
- Full Text :
- https://doi.org/10.1002/pros.20937