Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate cancer in TRAMP mice by inhibiting survival signaling

Abstract

In an extension of our previous studies showing potent antitumorigenic activity of synthetic triterpenoids of oleanolic acid against prostate cancer cell lines, we examined the efficacy of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preventing the development and/or progression of prostate cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Data show that oral gavage with CDDO (10 μmol/kg) for 20 weeks resulted in inhibition of the progression of preneoplastic lesions in the dorsolateral prostate and ventral prostate to adenocarcinoma without toxicity. CDDO also inhibited metastasis of tumor to the distant organs. Treatment with CDDO significantly inhibited cell proliferation, reduced the density of blood vessels and promoted apoptosis in the prostatic tissue. Further, Akt, NF-κB and NF-κB regulated Bcl-2, Bcl-xL, survivin and cIAP1 appear to be the molecular targets of CDDO for inhibiting the progression of prostate cancer in TRAMP mice. Thus, these studies show for the first time the potential of CDDO for chemoprevention of human prostate cancer.