CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma

Gao,Xiaohua; Deeb,Dorrah; Liu,Yongbo; Liu,Patricia; Zhang,Yiguan; Shaw,Jiajiu; Gautam,Subhash  C.

doi:10.3892/ijo.2015.3212

CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma

Authors:
- Xiaohua Gao
- Dorrah Deeb
- Yongbo Liu
- Patricia Liu
- Yiguan Zhang
- Jiajiu Shaw
- Subhash C. Gautam
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Affiliations: Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA
Published online on: October 19, 2015 https://doi.org/10.3892/ijo.2015.3212
Pages: 2100-2106

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Abstract

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.

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1	Pancreatic Cancer-National Cancer Institute. U.S. National Institutes of Health. Cancer Gov. http:www.cancer.gov/cancer-topics/types/pancreatic. Accessed April 6, 2010
2	Maitra A and Hruban RH: Pancreatic cancer. Annu Rev Pathol. 3:157–188. 2008. View Article : Google Scholar
3	Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar : PubMed/NCBI
4	Mulcahy MF, Wahl AO and Small W Jr: The current status of combined radiotherapy and chemotherapy for locally advanced or resected pancreas cancer. J Natl Compr Canc Netw. 3:637–642. 2005.PubMed/NCBI
5	Pino SM, Xiong HQ, McConkey D and Abbruzzese JL: Novel therapies for pancreatic adenocarcinoma. Curr Oncol Rep. 6:199–206. 2004. View Article : Google Scholar : PubMed/NCBI
6	Vaccaro V, Sperduti I and Milella M: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 365:768–769; author reply 769. 2011. View Article : Google Scholar : PubMed/NCBI
7	Kerr JF, Winterford CM and Harmon BV: Apoptosis. Its significance in cancer and cancer therapy. Cancer. 73:2013–2026. 1994. View Article : Google Scholar : PubMed/NCBI
8	Dzubak P, Hajduch M, Vydra D, Hustova A, Kvasnica M, Biedermann D, Markova L, Urban M and Sarek J: Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat Prod Rep. 23:394–411. 2006. View Article : Google Scholar : PubMed/NCBI
9	Huang MT, Ho CT, Wang ZY, Ferraro T, Lou YR, Stauber K, Ma W, Georgiadis C, Laskin JD and Conney AH: Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res. 54:701–708. 1994.PubMed/NCBI
10	Nishino H, Nishino A, Takayasu J, Hasegawa T, Iwashima A, Hirabayashi K, Iwata S and Shibata S: Inhibition of the tumor-promoting action of 12-O-tetradecanoylphorbol-13-acetate by some oleanane-type triterpenoid compounds. Cancer Res. 48:5210–5215. 1988.PubMed/NCBI
11	Ryu SY, Oak MH, Yoon SK, Cho DI, Yoo GS, Kim TS and Kim KM: Anti-allergic and anti-inflammatory triterpenes from the herb of Prunella vulgaris. Planta Med. 66:358–360. 2000. View Article : Google Scholar : PubMed/NCBI
12	Honda T, Rounds BV, Gribble GW, Suh N, Wang Y and Sporn MB: Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett. 8:2711–2714. 1998. View Article : Google Scholar
13	Suh N, Honda T, Finlay HJ, Barchowsky A, Williams C, Benoit NE, Xie QW, Nathan C, Gribble GW and Sporn MB: Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res. 58:717–723. 1998.PubMed/NCBI
14	Ito Y, Pandey P, Sporn MB, Datta R, Kharbanda S and Kufe D: The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. Mol Pharmacol. 59:1094–1099. 2001.PubMed/NCBI
15	Konopleva M, Tsao T, Estrov Z, Lee RM, Wang RY, Jackson CE, McQueen T, Monaco G, Munsell M, Belmont J, et al: The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia. Cancer Res. 64:7927–7935. 2004. View Article : Google Scholar : PubMed/NCBI
16	Gao X, Deeb D, Jiang H, Liu Y, Dulchavsky SA and Gautam SC: Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. J Neurooncol. 84:147–157. 2007. View Article : Google Scholar : PubMed/NCBI
17	Konopleva M, Contractor R, Kurinna SM, Chen W, Andreeff M and Ruvolo PP: The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells. Leukemia. 19:1350–1354. 2005. View Article : Google Scholar : PubMed/NCBI
18	Shishodia S, Sethi G, Konopleva M, Andreeff M and Aggarwal BB: A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin Cancer Res. 12:1828–1838. 2006. View Article : Google Scholar : PubMed/NCBI
19	Chintharlapalli S, Papineni S, Konopleva M, Andreef M, Samudio I and Safe S: 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways. Mol Pharmacol. 68:119–128. 2005.PubMed/NCBI
20	Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, et al: The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res. 65:4789–4798. 2005. View Article : Google Scholar : PubMed/NCBI
21	Deeb D, Gao X, Jiang H, Dulchavsky SA and Gautam SC: Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting prosurvival Akt and mTOR. Prostate. 69:851–860. 2009. View Article : Google Scholar : PubMed/NCBI
22	Chin YW, Balunas MJ, Chai HB and Kinghorn AD: Drug discovery from natural sources. AAPS J. 8:E239–E253. 2006. View Article : Google Scholar : PubMed/NCBI
23	Itokawa H, Morris-Natschke SL, Akiyama T and Lee KH: Plant-derived natural product research aimed at new drug discovery. J Nat Med. 62:263–280. 2008. View Article : Google Scholar : PubMed/NCBI
24	Gao X, Deeb D, Liu Y, Arbab AS, Divine GW, Dulchavsky SA and Gautam SC: Prevention of prostate cancer with oleanane synthetic triterpenoid CDDO-Me in the TRAMP mouse model of prostate cancer. Cancers (Basel). 3:3353–3369. 2011. View Article : Google Scholar
25	Deeb D, Gao X, Liu Y, Jiang D, Divine GW, Arbab AS, Dulchavsky SA and Gautam SC: Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate cancer in TRAMP mice by inhibiting survival signaling. Carcinogenesis. 32:757–764. 2011. View Article : Google Scholar : PubMed/NCBI
26	Ling X, Konopleva M, Zeng Z, Ruvolo V, Stephens LC, Schober W, McQueen T, Dietrich M, Madden TL and Andreeff M: The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling. Cancer Res. 67:4210–4218. 2007. View Article : Google Scholar : PubMed/NCBI
27	Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, Honda T, Gribble GW, Dmitrovsky E, Sporn TA and Sporn MB: The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res. 67:2414–2419. 2007. View Article : Google Scholar : PubMed/NCBI
28	Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:231–241. 1997. View Article : Google Scholar : PubMed/NCBI
29	Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96:857–868. 1999. View Article : Google Scholar : PubMed/NCBI
30	Karin M, Cao Y, Greten FR and Li ZW: NF-kappaB in cancer: From innocent bystander to major culprit. Nat Rev Cancer. 2:301–310. 2002. View Article : Google Scholar : PubMed/NCBI
31	Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 18:1926–1945. 2004. View Article : Google Scholar : PubMed/NCBI