Antiproliferative Activity of Double Point Modified Analogs of 1,25-Dihydroxyvitamin D2 Against Human Malignant Melanoma Cell Lines

International Journal of Molecular Sciences

Anna Piotrowska³  Justyna Wierzbicka³  Sharmin Nadkarni⁴  Geoffrey Brown²  Andrzej Kutner⁴  Michał A. Żmijewski³  Roman Perez-Fernandez¹ 

[1] Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 1a Debinki, Gdańsk 80-211, PolandSchool of Immunity and Infection, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, West Midlands B15 2TT, UK;Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 1a Debinki, Gdańsk 80-211, Poland;Pharmaceutical Research Institute, 8 Rydygiera, Warsaw 01-793, Poland;

关键词: vitamin D;    vitamin D₂;    novel vitamin D analogs;    melanoma;    skin cancer;    VDR;   

DOI  :  10.3390/ijms17010076

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2016 by the authors; licensee MDPI, Basel, Switzerland.