Chemoprevention of chemically-induced mammary and colon carcinogenesis by 1alpha-hydroxyvitamin D5.
Epidemiological data as well as experimental models yield evidence for a protective effect of vitamin D against the genesis of several types of cancers. Given its toxic properties at effective concentrations, numerous analogs of vitamin D have been developed. We synthesized an analog of vitamin D(5), 1alpha-hydroxy-24-ethylcholechalciferol (1alpha(OH)D(5)) and previously reported on its anti-proliferative activities against several cancer cell lines. To further examine its chemopreventive potential, experiments were conducted to investigate the in vivo effects of 1alpha(OH)D(5) using the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model. Results showed that 1alpha(OH)D(5) (25 and 50microg/kg diet) decreased the incidence and multiplicity of mammary tumors in female Sprague-Dawley rats. In a subsequent study, the stage specific inhibition was investigated using the 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis model. While supplementation with of 1alpha(OH)D(5) (40microg/kg diet) showed no significant effects during the initiation phase, tumor incidence during the promotional stage was significantly (p<0.05) decreased by 37.5%. In the colon, 1alpha(OH)D(5) (25microg/kg diet) was highly effective (p<0.001) in inhibiting the development of azoxymethane (AOM)-induced Aberrant crypt foci (ACF) in CF-1 mice. Studies on the stage specific inhibitory effects of 1alpha(OH)D(5) in the colon demonstrated that animals receiving 1alpha(OH)D(5) (25microg/kg diet) during the initiation, promotion, and entire period had a reduction in ACF number of 71, 80 and 82%, respectively. Immunohistochemistry studies comparing the colons of animals receiving control versus 1alpha(OH)D(5) supplemented diets showed that 1alpha(OH)D(5) partly mediates its effects by regulating members of the oncogenic beta-catenin pathway. 1Alpha(OH)D(5) inhibited expression of beta-catenin and peroxisome proliferator-activated receptor beta, a beta-catenin-TCF-4 responsive gene, whereas it induced expression of VDR. Cumulatively, these studies support the chemopreventive properties of 1alpha(OH)D(5) against the development of breast and colon cancers.
Murillo
Genoveva
G
Carcinogenesis and Chemoprevention Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616, USA.
Mehta
Rajendra G
RG
D000818:Animals; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004032:Diet; D005260:Female; D006887:Hydroxycholecalciferols / Q000494:pharmacology* / Q000627:therapeutic use; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000494:pharmacology; D008968:Molecular Conformation; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D051155:Wnt1 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C103958:1-hydroxyvitamin D5; D006887:Hydroxycholecalciferols; D051155:Wnt1 Protein; D051176:beta Catenin; D008770:Methylnitrosourea