2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic
acid (
CDDO), a synthetic analog of
oleanolic acid, and its C28 methyl
ester derivative (
CDDO-Me), have shown potent antitumorigenic activity against a wide range of
cancer cell lines, including
prostate cancer cells in vitro, and inhibited the development of liver and
lung cancer in vivo. In the present study, we examined the efficacy of
CDDO-Me in preventing the development and progression of
prostate cancer in the transgenic adenocarinoma of the mouse prostate (TRAMP) model.
CDDO-Me inhibited the growth of murine TRAMPC-1
prostate cancer cells by inducing apoptosis through the inhibition of antiapoptotic p-Akt, p-mTOR and NF-κB. Early intervention with
CDDO-Me (7.5 mg/kg) initiated at five weeks of age for 20 wk inhibited the progression of the preneoplastic lesions (low-grade PIN and high-grade-PIN) to
adenocarcinoma in the dorsolateral prostate (DLP) and ventral prostate (VP) lobes of TRAMP mice. Even delayed administration of
CDDO-Me started at 12 wk of age for 12 wk inhibited the development of adenocarcimona of the prostate. Both early and late treatment with
CDDO-Me inhibited the
metastasis of
tumor to the distant organs. Treatment with
CDDO-Me inhibited the expression of prosurvival p-Akt and NF-κB in the prostate and knocking-down Akt in TRAMPC-1
tumor cells sensitized them to
CDDO-Me. These findings indicated that Akt is a target for apoptoxicity in TRAMPC-1 cells in vitro and potentially a target of
CDDO-Me for inhibition of
prostate cancer in vivo.