Chemoprevention of chemically-induced mammary and colon carcinogenesis by 1alpha-hydroxyvitamin D5.

Abstract

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.

• Authors: Genoveva Murillo, Rajendra G Mehta
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 97 Issue 1-2 Pg. 129-36 (Oct 2005) ISSN: 0960-0760 [Print] England
• PMID: 16051482 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1-hydroxyvitamin D5
• Hydroxycholecalciferols
• Wnt1 Protein
• beta Catenin
• Methylnitrosourea

Topics

• Animals
• Chemoprevention
• Colonic Neoplasms (drug therapy, metabolism, pathology, prevention & control)
• Diet
• Female
• Hydroxycholecalciferols (pharmacology, therapeutic use)
• Mammary Glands, Animal (drug effects, pathology)
• Mammary Neoplasms, Experimental (drug therapy, pathology, prevention & control)
• Methylnitrosourea (pharmacology)
• Molecular Conformation
• Organ Specificity
• Rats
• Rats, Sprague-Dawley
• Wnt1 Protein (metabolism)
• beta Catenin (metabolism)