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Int. J. Mol. Sci. 2015, 16(10), 24873-24894; doi:10.3390/ijms161024873

Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol

1
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla, 53-114 Wrocław, Poland
2
Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland
3
Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University, 13/15 Armii Krajowej Ave., 42-200 Częstochowa, Poland
These authors contributed equally to this study.
*
Author to whom correspondence should be addressed.
Academic Editor: Roman Perez-Fernandez
Received: 21 September 2015 / Revised: 30 September 2015 / Accepted: 9 October 2015 / Published: 20 October 2015
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Abstract

Analogs of 1,25-dihydroxyergocalciferol, modified in the side-chain and in the A-ring, were tested for their antiproliferative activity against a series of human cancer cell lines in vitro and in vivo toxicity. The proliferation inhibition caused by the analogs was higher than that of the parent compounds, while the toxicity, measured as the serum calcium level, was lower. All analogs were able to induce, in HL-60 and MV4-11 leukemic cells, G0/G1 cell cycle arrest and differentiation expressed as morphological signs typical for monocytes. The analogs also induced the expression of CD11b and/or CD14 cell-differentiation markers. The most potent analogs, PRI-5105, PRI-5106, PRI-5201 and PRI-5202, were also able to induce vitamin D receptor (VDR) protein expression, mainly in the cytoplasmic fraction of HL-60 or MV4-11 cells. The most active analogs were the 19-nor ones with an extended and rigidified side-chain (PRI-5201 and PRI-5202), as in the former analogs PRI-1906 and PRI-1907. Epimerization at C-24 (PRI-5101) or introduction of an additional hydroxyl at C-23 (PRI-5104) reduced the toxicity of the analog with retained antiproliferative activity. View Full-Text
Keywords: calcitriol and analogs; 1,25-dihydroxyergocalciferol analogs; human cancer cell lines; antiproliferative activity in vitro; CD11b and CD14 cell-surface markers; cytoplasmic vacuolization; cell cycle; VDR and MARRS mRNA expression calcitriol and analogs; 1,25-dihydroxyergocalciferol analogs; human cancer cell lines; antiproliferative activity in vitro; CD11b and CD14 cell-surface markers; cytoplasmic vacuolization; cell cycle; VDR and MARRS mRNA expression
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Trynda, J.; Turlej, E.; Milczarek, M.; Pietraszek, A.; Chodyński, M.; Kutner, A.; Wietrzyk, J. Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol. Int. J. Mol. Sci. 2015, 16, 24873-24894.

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