title: Antiproliferative Activity of Double Point Modified Analogs of 1,25-Dihydroxyvitamin D₂ Against Human Malignant Melanoma Cell Lines.
abstract: Vitamin D is a lipid soluble steroid hormone with pleiotropic biological properties, including regulation of cell proliferation, differentiation and apoptosis. As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of a wide variety of cancer cell types, including human malignant melanoma. However, there is a need for novel and more efficacious vitamin D analogs, and how best to design such is still an open issue. A series of double point modified (DPM) analogs of 1,25-dihydroxyvitamin D₂ (1,25(OH)₂D₂) induced differentiation of the vitamin D receptor (VDR) positive A375 and VDR negative SK-MEL 188b human malignant melanoma cell lines. Surprisingly, the dose of 1,25(OH)₂D₂ required to inhibit the proliferation of the A375 melanoma cell line by was several fold lower than that required in the case of 1,25(OH)₂D₃. To evaluate the impact of the modification in the side chain (additional 22-hydroxyl) and in the A-ring (5,6-trans modification), the regular side-chain of vitamin D₂ or D₃ was retained in the structure of our analogs. As expected, 5,6-trans modification was advantageous to enhancing the anti-proliferative activity of analogs, but not as a single point modification (SPM). Very unexpectedly, the additional 22-hydroxyl in the side-chain reduced significantly the anti-proliferative activity of both the natural and 5,6-trans series analogs. Finally, an induction of pigmentation in melanoma SK-MEL 188b cells was observed to sensitized cells to the effect of vitamin D analogs.
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 1a Debinki, Gdańsk 80-211, Poland. annapiotrowska@gumed.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Piotrowska
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 1a Debinki, Gdańsk 80-211, Poland. jwierzbicka@gumed.edu.pl.
authors.forename: Justyna
authors.initials: J
authors.lastname: Wierzbicka
authors.affiliation: Pharmaceutical Research Institute, 8 Rydygiera, Warsaw 01-793, Poland. s.nadkarni@ifarm.eu.
authors.forename: Sharmin
authors.initials: S
authors.lastname: Nadkarni
authors.affiliation: School of Immunity and Infection, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, West Midlands B15 2TT, UK. g.brown@bham.ac.uk.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Brown
authors.affiliation: Pharmaceutical Research Institute, 8 Rydygiera, Warsaw 01-793, Poland. a.kutner@ifarm.eu.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kutner
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 1a Debinki, Gdańsk 80-211, Poland. mzmijewski@gumed.edu.pl.
authors.forename: Michał A
authors.initials: MA
authors.lastname: Żmijewski
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004872:Ergocalciferols / Q000737:chemistry* / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018167:Receptors, Calcitriol / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000970:Antineoplastic Agents; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C003564:1,25-dihydroxyergocalciferol
keywords: VDR; melanoma; novel vitamin D analogs; skin cancer; vitamin D; vitamin D2