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Journal of Cancer Research and Clinical Oncology

Published in:

01-01-2008 | Original Paper

Ursolic acid inhibits the formation of aberrant crypt foci and affects colonic sphingomyelin hydrolyzing enzymes in azoxymethane-treated rats

Authors: David Andersson, Yajun Cheng, Rui-Dong Duan

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2008

Abstract

Ursolic acid (UA) is a pentacyclic triterpenoid, with anti-cancer and anti-inflammatory properties. Sphingomyelin (SM) hydrolysis generates lipid messengers regulating cell survival. Earlier studies showed that UA has anti-proliferative and apoptotic effects on HT29 cells, accompanied by a rapid increase in alkaline sphingomyelinase (Alk-SMase) activity. This study examines the effect of orally administered UA on the formation of aberrant crypt foci (ACF) and intestinal SMase activity in azoxymethane (AOM)-treated rats. Sprague-Dawley rats were divided into eight groups, receiving AOM or vehicle, and fed normal diet or pellets containing 0.11% UA in the initiation or promotion/progression phase. The formation of ACF in the colon and the activities of three types of mucosal SMase were examined. UA significantly reduced the incidence of ACF containing three or more crypts in the initiation group, but had no significant effect in the promotion/progression group. AOM reduced mucosal Alk-SMase activity, and the inhibitory effects could not be prevented by UA. However, in both AOM-treated and normal rats, UA increased the activity of colonic neutral SMase markedly and that of acid SMase activity mildly. These results indicate that UA has chemopreventive effects in the initiation phase of colon cancer associated with changes in SM metabolism.

Andersson D, Liu JJ, Nilsson A, Duan RD (2003) Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase. Anticancer Res 4:3317–3322

Andersson D, Nilsson Å, Duan R-D (2006) Ursolic acid and other pentacyclic triterpenoids stimulate intestinal alkaline sphingomyelinase in vitro. Eur J Lipid Sci Technol 2:103–108CrossRef

Bird RP (1987) Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 2:147–151CrossRef

Bird RP, Good CK (2000) The significance of aberrant crypt foci in understanding the pathogenesis of colon cancer. Toxicol Lett 112–113:395–402PubMedCrossRef

Chan TA, Morin PJ, Vogelstein B, Kinzler KW (1998) Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci USA 2:681–686CrossRef

Chatterjee S (1999) Neutral sphingomyelinase: past, present and future. Chem Phys Lipids 1–2:79–96CrossRef

Duan RD, Nilsson A (2000) Sphingolipid hydrolyzing enzymes in the gastrointestinal tract. Methods Enzymol 311:276–286PubMedCrossRef

Duan RD, Nyberg L, Nilsson A (1995) Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics. Biochim Biophys Acta 1:49–55

Duan RD, Bergman T, Xu N, Wu J, Cheng Y, Duan J et al (2003) Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family. J Biol Chem 40:38528–38536CrossRef

Goni FM, Alonso A (2002) Sphingomyelinases: enzymology and membrane activity. FEBS Lett 1:38–46CrossRef

Gulbins E, Li PL (2006) Physiological and pathophysiological aspects of ceramide. Am J Physiol Regul Integr Comp Physiol 1:R11–R26

Hertervig E, Nilsson A, Nyberg L, Duan RD (1997) Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma. Cancer 3:448–453CrossRef

Hertervig E, Nilsson A, Bjork J, Hultkrantz R, Duan RD (1999) Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation? Br J Cancer 2:232–236CrossRef

Hertervig E, Nilsson A, Cheng Y, Duan RD (2003) Purified intestinal alkaline sphingomyelinase inhibits proliferation without inducing apoptosis in HT-29 colon carcinoma cells. J Cancer Res Clin Oncol 10:577–582CrossRef

Jayadev S, Linardic CM, Hannun YA (1994) Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor alpha. J Biol Chem 8:5757–5763

Kochanek KD, Murphy SL, Anderson RN, Scott C (2004) Deaths: final data for 2002. Natl Vital Stat Rep 5:1–115

Lemonnier LA, Dillehay DL, Vespremi MJ, Abrams J, Brody E, Schmelz EM (2003) Sphingomyelin in the suppression of colon tumors: prevention versus intervention. Arch Biochem Biophys 2:129–138CrossRef

Lillienau J, Crombie DL, Munoz J, Longmire-Cook SJ, Hagey LR, Hofmann AF (1993) Negative feedback regulation of the ileal bile acid transport system in rodents. Gastroenterology 1:38–46

Liu J (1995) Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 2:57–68CrossRef

Liu F, Cheng Y, Wu J, Tauschel HD, Duan RD (2006) Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells. Cancer Lett 1:141–146CrossRef

Marchesini N, Hannun YA (2004) Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 1:27–44CrossRef

Marchesini N, Osta W, Bielawski J, Luberto C, Obeid LM, Hannun YA (2004) Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. J Biol Chem 24:25101–25111CrossRef

Najid A, Simon A, Cook J, Chable-Rabinovitch H, Delage C, Chulia AJ et al (1992) Characterization of ursolic acid as a lipoxygenase and cyclooxygenase inhibitor using macrophages, platelets and differentiated HL60 leukemic cells. FEBS Lett 3:213–217CrossRef

Novotny L, Vachalkova A, Biggs D (2001) Ursolic acid: an anti-tumorigenic and chemopreventive activity. Minireview. Neoplasma 4:241–246

Pretlow TP, O’Riordan MA, Somich GA, Amini SB, Pretlow TG (1992) Aberrant crypts correlate with tumor incidence in F344 rats treated with azoxymethane and phytate. Carcinogenesis 9:1509–1512CrossRef

Ringbom T, Segura L, Noreen Y, Perera P, Bohlin L (1998) Ursolic acid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis. J Nat Prod 10:1212–1215CrossRef

Selzner M, Bielawska A, Morse MA, Rudiger HA, Sindram D, Hannun YA et al (2001) Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res 3:1233–1240

Sjoqvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B et al (2002) Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity. Inflamm Bowel Dis 4:258–263CrossRef

Spiegel S, Merrill AH Jr (1996) Sphingolipid metabolism and cell growth regulation. Faseb J 12:1388–1397

Stoffel W (1975) Chemical synthesis of choline-labeled lecithins and sphingomyelins. Methods Enzymol 35:533–541PubMed

Subbaramaiah K, Michaluart P, Sporn MB, Dannenberg AJ (2000) Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res 9:2399–2404

Takahashi M, Wakabayashi K (2004) Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents. Cancer Sci 6:475–480CrossRef

Wu J, Cheng Y, Jonsson BA, Nilsson A, Duan RD (2005) Acid sphingomyelinase is induced by butyrate but does not initiate the anticancer effect of butyrate in HT29 and HepG2 cells. J Lipid Res 9:1944–1952CrossRef

Wu M, Harvey KA, Ruzmetov N, Welch ZR, Sech L, Jackson K et al (2005) Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway. Int J Cancer 3:340–348CrossRef

Title: Ursolic acid inhibits the formation of aberrant crypt foci and affects colonic sphingomyelin hydrolyzing enzymes in azoxymethane-treated rats
Authors: David Andersson
Yajun Cheng
Rui-Dong Duan
Publication date: 01-01-2008
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2008
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-007-0255-4

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