Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (
CDDO-Me) has shown potent antitumorigenic activity against a wide range of
cancer cell lines in vitro and inhibited the growth of liver, lung and
prostate cancer in vivo. In the present study, we examined the antitumor activity of
CDDO-Me for pancreatic ductal
adenocarcinoma (PDAC) cells with and without activating K-ras mutations. Treatment of K-ras mutant MiaPaCa-2 and K-ras normal BxPC-3 cells with
CDDO-Me elicited strong antiproliferative and proapoptopic responses in both cell lines in culture. The inhibition of cell proliferation and induction of apoptosis was accompanied by the inhibition of antiapoptotic/prosurvival p-Akt, NF-кB and p-mTOR signaling
proteins. For testing efficacy of
CDDO-Me in vivo heterotopic and orthotopic xenografts were generated by implanting BxPC-3 and MiaPaCa-2 cells subcutaneously and in the pancreatic tail, respectively. Treatment with
CDDO-Me significantly inhibited the growth of BxPC-3 xenografts and reduced the levels of p-Akt and p-mTOR in
tumor tissue. In mice with orthotopic MiaPaCa-2 xenografts, treatment with
CDDO-Me prolonged the survival of mice when administered following the surgical resection of
tumors. The latter was attributed to the eradication of residual PDAC remaining after resection of
tumors. These preclinical data demonstrate the potential of
CDDO-Me for treating primary PDAC
tumors and for preventing relapse/recurrence through the destruction of residual disease.