Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D 3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells

Diego Iglesias-Gato, Shasha Zheng, John N. Flanagan, Lan Jiang, Atsushi Kittaka, Toshiyuki Sakaki, Keiko Yamamoto, Toshimasa Itoh, Nathan K. Lebrasseur, Gunnar Norstedt, Tai C. Chen

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The active form of vitamin D 3, 1α,25-dihydroxyvitamin D 3(1α,25(OH) 2D 3), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH) 2D 3 therapeutic potential in treating cancers, numerous analogues have been synthesized with an attempt to increase anti-proliferative and/or decrease calcemic properties. Among these analogues, 19-nor-1α,25(OH) 2D 2 while being less calcemic has equivalent potency as 1α,25(OH) 2D 3 in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3- hydroxypropyl)-1α,25(OH) 2D 3 (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH) 2D 3 in inhibiting the proliferation of an immortalized normal prostate PZ-HPV-7 cells and the invasion of androgen insensitive PC-3 prostate cancer cells, respectively. In this study, we further investigated the effects of MART-10 and 1α,25(OH) 2D 3 on the dose- and time-dependent induction of CYP24A1 gene expression in PC-3 prostate cancer cells. We found that MART-10 induced CYP24A1 gene expression at a lower concentration with a longer duration compared to 1α,25(OH) 2D 3, suggesting that MART-10 is less susceptible to CYP24A1 degradation. Molecular docking model of human CYP24A1 and MART-10 indicates that its side chain is far away from the heme ion and is less likely to be hydroxylated by the enzyme. Furthermore, MART-10 was a more potent inhibitor of PC-3 cell proliferation and invasion compared to 1α,25(OH) 2D 3. In addition, MART-10 down-regulated matrix metalloproteinase-9 (MMP-9) expression which could be one mechanism whereby MART-10 influences cancer cell invasion. Finally, we observed that subcutaneous administration of MART-10 up-regulated the CYP24A1 mRNA expression in rat kidneys without affecting their plasma calcium levels. Thus, our findings demonstrate that MART-10 is biologically active in vivo and may be an effective vitamin D analogue for clinical trials to treat prostate cancer.

Original languageEnglish (US)
Pages (from-to)269-275
Number of pages7
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume127
Issue number3-5
DOIs
StatePublished - Nov 1 2011

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Keywords

  • Invasion
  • PC-3
  • Proliferation
  • Prostate cancer
  • Vitamin D analogue

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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