title: Noncalcemic 20-hydroxyvitamin D3 inhibits human melanoma growth in in vitro and in vivo models.
abstract: 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)D3in 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.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, AL, USA.|Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University in Torun, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Skobowiat
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, AL, USA.
authors.forename: Allen S W
authors.initials: AS
authors.lastname: Oak
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, AL, USA.
authors.forename: Tae-Kang
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tuckey
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, AL, USA.|Laboratory Service of the VA Medical Center, Birmingham, AL, USA.|Comprehensive Cancer Center Cancer Chemoprevention Program, University of Alabama at Birmingham, AL, USA.|Nutrition Obesity Research Center, University of Alabama at Birmingham, AL, USA.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C480634:20-hydroxyvitamin D3; D000970:Antineoplastic Agents; D002112:Calcifediol
keywords: SKMel-188; melanoma; mice; pre-clinical; vitamin D