Noncalcemic 20-hydroxyvitamin D3 inhibits human melanoma growth in in vitro and in vivo models
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Cezary Skobowiat1,2,*, Allen S.W. Oak1,*, Tae-Kang Kim1, Chuan He Yang3, Lawrence M. Pfeffer3, Robert C. Tuckey4, Andrzej T. Slominski1,5,6,7
1Department of Dermatology, University of Alabama at Birmingham, AL, USA
2Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University in Torun, Poland
3Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA
4School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA, Australia
5Laboratory Service of the VA Medical Center, Birmingham, AL, USA
6Comprehensive Cancer Center Cancer Chemoprevention Program, University of Alabama at Birmingham, AL, USA
7Nutrition Obesity Research Center, University of Alabama at Birmingham, AL, USA
*These authors have contributed equally to this work
Andrzej T. Slominski, email: [email protected]
Keywords: melanoma, pre-clinical, SKMel-188, vitamin D, mice
Received: September 09, 2016 Accepted: November 23, 2016 Published: December 26, 2016
A novel pathway of vitamin D3 (D3) metabolism, initiated by C20-hydroxylation of D3 by CYP11A1, has been confirmed to operate in vivo. Its major product, 20(OH)D3, exhibits antiproliferative activity in vitro comparable to that of 1,25(OH)2D3, but is noncalcemic in mice and rats. To further characterize the antimelanoma activity of 20(OH)D3, we tested its effect on colony formation of human melanoma cells in monolayer culture and anchorage-independent growth in soft agar. The migratory capabilities of the cells and cell-cell and cell-extracellular matrix interactions were also evaluated using transwell cell migration and spheroid toxicity assays. To assess the antimelanoma activity of 20(OH)D3 in vivo, age-matched immunocompromised mice were subcutaneously implanted with luciferase-labelled SKMel-188 cells and were randomly assigned to be treated with either 20(OH)D3 or vehicle (n=10 per group). Tumor size was measured with caliper and live bioimaging methods, and overall health condition expressed as a total body score scale. The following results were observed: (i) 20(OH)D3 inhibited colony formation both in monolayer and soft agar conditions, (ii) 20(OH)D3 inhibited melanoma cells in both transwell migration and spheroid toxicity assays, and (iii) 20(OH)D3 inhibited melanoma tumor growth in immunocompromised mice without visible signs of toxicity. However, although the survival rate was 90% in both groups, the total body score was higher in the treatment group compared to control group (2.8 vs. 2.55). In conclusion, 20(OH)D3, an endogenously produced secosteroid, is an excellent candidate for further preclinical testing as an antimelanoma agent.
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