Chemoprevention of Colon Carcinogenesis by Oleanolic Acid and Its Analog in Male F344 Rats and Modulation of COX-2 and Apoptosis in Human Colon HT-29 Cancer Cells
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To assess the chemopreventive effect of oleanolic acid (ONA) and its synthetic analog 18α-olean-12-ene-3β-23,28-triol (OT) on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in F344 rats and understand anti-inflammatory properties and apoptosis effects in HT29 colon cancer cells and Raw 264.7 macrophage cell lines.
Five week-old male F344 rats were fed a control diet or experimental diets containing two doses of ONA (750 and 1,500 ppm) and OT (250 and 500 ppm). After 1 week, all animals were s.c. injected with AOM (15 mg/kg body weight, once weekly for 2 weeks). At 14 weeks of age, all rats were killed and colons were evaluated for ACF. Cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expressions and apoptosis were assessed in cell lines exposed to OT using western blots and 4’,6-diamidino-2-phenylindole staining.
Administration of ONA and OT inhibited mean colonic ACF and multi-crypt AC/foci in a dose dependent manner (p < 0.001–0.0001). OT blocked the COX-2 expression induced by phorbol 12-myristate 13-acetate in a dose-dependent manner and induced apoptosis in HT-29 cancer cells, and suppressed iNOS activation in RAW264.7 macrophages.
ONA and OT possess chemopreventive activity against colon carcinogenesis in rat and OT inhibits the COX-2 and iNOS and induces apoptosis in cell lines.
Key wordschemoprevention colon cancer COX-2 iNOS triterpenoids
We gratefully acknowledge NCI chemoprevention drug development repository for providing oleanolic acid analog OT. We also extend our thanks to Ms. Alyson Atchison for editing this article.
- 4.N. Suh, Y. Wang, T. Honda, G. W. Gribble, E. Dmitrovsky, W. F. Hickey, R. A. Maue, A. E. Place, D. M. Porter, M. J. Spinella, C. R. Williams, G. Wu, A. J. Dannenberg, K. C. Flanders, J. J. Letterio, D. J. Mangelsdorf, C. F. Nathan, L. Nguyen, W. W. Porter, R. F. Ren, N. S. Roche, K. Subbaramaiah, and M. B. Sporn. A novel synthetic oleanane triterpenoid, 2-cyno-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating antiproliferative and anti-inflammatory activity. Cancer Res. 59:336–341 (1999).PubMedGoogle Scholar
- 5.B. J. Naveena, and C. V. Rao. Molecular markers and targets for colorectal cancer prevention. Acta Pharmacologica Sinica. 29:1–20 (2008).Google Scholar
- 7.C. V. Rao, C. Indranie, B. Simi, P. T. Manning, J. R. Connor, and B. S. Reddy. Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxygenase-2 inhibitor. Cancer Res. 62(1):165–70 (2002).PubMedGoogle Scholar
- 18.C. Indranie, S. V. Malisetty, P. Jagan, L. E. S. Joel, V. E. Steele, and C. V. Rao. Chemoprevention of colon carcinogenesis by oleanolic acid and its analog in male F344rats and modulation of iNOS, COX-2 and apoptosis in human colon HT-29 cancer cells. AACR Proceeding. Abstract No. 819. 43:164–164 (2002).Google Scholar
- 22.R. Jayadev, M. R. P. Jagan, V. S. Malisetty, and C. V. Rao. Colon cancer preventive effects of Trigonella foenum graecum (fenugreek) seed and its constituent diosgenin in vivo and in vitro. Cancer Epidemiol. Biomarkers Prev. 13:1392–1398 (2004).Google Scholar
- 23.T. Kawamoori, T. Tanaka, A. Hara, J. Yamahara, and H. Mori. Modifying effects of naturally occurring products on the development of colonic aberrant crypt foci by azoxymethane in F344 rats. Cancer Res. 55:1277–1282 (1995).Google Scholar
- 24.H. Ohigashi, H. Takamura, K. Koshimizu, H. Tokuda, and Y. Ito. Search for possible antitumor promoters by inhibition of n-O-tetradecanoylphorbol-B-acetate induced Epstein–Barr virus activation: ursolic acid and oleanolic acid from an anti-inflammatory Chinese medicinal plant, Glechoma hederaceae L. Cancer Lett. JO:143–151 (1986).CrossRefGoogle Scholar
- 33.G. Steinbach, P. M. Lynch, R. K. Phillips, M. H. Wallace, E. Hawk, G. B. Gordon, N. Wakabayashi, B. Saunders, Y. Shen, T. Fujimura, L. K. Su, and B. Levin. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342:1946–1952 (2000).PubMedCrossRefGoogle Scholar
- 38.S. D. Solomon, J. J. V. McMurray, M. A. Pfeffer, J. Wittes, R. Fowler, P. Finn, W. F. Anderson, A. Zauber, E. Hawk, and M. Bertagnolli. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352:1071–1080 (2005).PubMedCrossRefGoogle Scholar
- 39.A. Rostom, C. Dubé, G. Lewin, A. Tsertsvadze, N. Barrowman, and C. Code. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. preventive services task force. Ann. Intern. Medicine. 146:376–89 (2007).Google Scholar