Antiproliferative activity of double point modified analogs of 1,25-dihydroxyvitamin D₂ against human malignant melanoma cell lines

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Authors

  • Anna Piotrowska
  • Justyna Wierzbicka
  • Sharmin Nadkarni
  • Andrzej Kutner
  • Michał A Żmijewski

Colleges, School and Institutes

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.

Details

Original languageEnglish
Article number76
Pages (from-to)1-16
Number of pages16
JournalInternational Journal of Molecular Sciences
Volume17
Issue number1
Publication statusPublished - 8 Jan 2016

Keywords

  • vitamin D, vitamin D2, novel vitamin D analogs, melanoma, skin cancer, VDR