Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis
Sung Hee Choi, … , Sanford D. Markowitz, John J. Letterio
Sung Hee Choi, … , Sanford D. Markowitz, John J. Letterio
Published May 16, 2014
Citation Information: J Clin Invest. 2014;124(6):2472-2482. https://doi.org/10.1172/JCI69672.
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Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis

Abstract

Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1β; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro. Furthermore, CDDO-Me–dependent 15-PGDH induction was not observed in Smad3–/– mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate–induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.

Authors

Sung Hee Choi, Byung-Gyu Kim, Janet Robinson, Steve Fink, Min Yan, Michael B. Sporn, Sanford D. Markowitz, John J. Letterio

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Figure 5

Chemoprevention of AOM/DSS-induced colon cancer by CDDO-Me.

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Chemoprevention of AOM/DSS-induced colon cancer by CDDO-Me. Body weight ...
Body weight and tumor number in mice treated with AOM/DSS or AOM/DSS plus CDDO-Me. (A) Experimental procedure used to induce colon cancer in C57BL/6 mice. After initial AOM injection (10 mg/kg), DSS was given in drinking water, followed by normal drinking water. Either CDDO-Me (250 ng per mouse per day) or sesame oil were given to the mice every other day during the DSS treatment. (B) Changes in body weight among each group were defined as follows: percentage = (final weight – initial weight)/initial weight × 100. CDDO-ME treatment did not affect the body weights. Tumors were enumerated examined using a dissecting microscope at day 53. (C) Images of colons at necropsy and (D) H&E staining of tumor morphology. Scale bar: 200 μM. (E) Colon length and (F) number of tumors in sesame oil–treated or CDDO-ME–treated groups. The sesame oil–treated group had 10 mice, and the CDDO-ME–treated group had 9 mice. Results are mean ± SEM. **P < 0.01.