CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma.
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.
Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Xiaohua
X
Gao
Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Dorrah
D
Deeb
Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Yongbo
Y
Liu
Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Patricia
P
Liu
Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
Yiguan
Y
Zhang
Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
Jiajiu
J
Shaw
Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Subhash C
SC
Gautam
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009828:Oleanolic Acid; C445068:bardoxolone methyl