title: Chemopreventive effect of farnesol and lanosterol on colon carcinogenesis.
abstract: Cholesterol metabolites play a several critical roles in regulating cell growth and function. 3-Hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the rate-limiting enzyme for this pathway, is down regulated by feedback mechanisms due to increased levels of cholesterol and its premetabolites. Several HMG-CoA metabolites, such as farnesyl pyrophosphate and geranyl pyrophosphate are implicated in oncogene activation and tumorigenesis. Recent studies suggest that inhibition of HMG-CoA reductase by specific inhibitors or by naturally-occurring phytochemicals, such as farnesol or squalene can modulate tumor cell growth. Thus, in this study, we have assessed the chemopreventive efficacy of farnesol and lanosterol on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. In addition, we measured the effect of farnesol and lanosterol on serum high denisity lipoprotein (HDL) and cholesterol levels in the rats. Seven-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing I or 2% lanosterol or 1.5% farnesol. One week later, all animals except those in vehicle (normal saline)-treatment groups were s.c. injected with AOM (15 mg/kg body weight, once weekly for 2 weeks). At 16 weeks of age, all rats were killed, colons were evaluated for ACF and serum was assayed for HDL and cholesterol levels. Administration of dietary farnesol significantly inhibited ACF formation by about 34% (P < 0.001) and reduced crypt multiplicity by about 44% (P < 0.0001). Also, administration of lanosterol at dose levels of I or 2 % in the diet significantly suppressed AOM-induced colonic ACF as well as multicrypt foci formation. (P < 0.01-0.001). Further, farnesol at 1.5% and lanosterol at 1% did not show any significant effect on serum HDL nor on total cholesterol levels. However, lanosterol at 2% significantly increased serum HDL (P < 0.05) and cholesterol (P < 0.01) levels. That farnesol and lanosterol significantly suppress colonic ACF formation and crypt multiplicity strengthens the hypothesis that these agents possess chemopreventive activity against colon carcinogenesis.
authors.affiliation: Division of Nutritional Carcinogenesis, American Health Foundation, One Dana Road, Valhalla, NY 10595, USA. crao@ahf.org
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
authors.forename: Harold L
authors.initials: HL
authors.lastname: Newmark
authors.forename: Bandaru S
authors.initials: BS
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002784:Cholesterol / Q000097:blood; D003110:Colonic Neoplasms / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D005204:Farnesol / Q000494:pharmacology*; D007810:Lanosterol / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D011230:Precancerous Conditions / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D008075:Lipoproteins, HDL; D007810:Lanosterol; D005204:Farnesol; D002784:Cholesterol; D001397:Azoxymethane