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Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

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

The active form of vitamin D(3), 1α,25-dihydroxyvitamin D(3)(1α,25(OH)(2)D(3)), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH)(2)D(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)(2)D(2) while being less calcemic has equivalent potency as 1α,25(OH)(2)D(3) in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH)(2)D(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)(2)D(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)(2)D(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)(2)D(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.

OriginalsprogEngelsk
TidsskriftJournal of Steroid Biochemistry and Molecular Biology
Vol/bind127
Udgave nummer3-5
Sider (fra-til)269-75
Antal sider7
ISSN0960-0760
DOI
StatusUdgivet - 2011
Eksternt udgivetJa

    Forskningsområder

  • Antineoplastic Agents, Blotting, Western, Calcitriol, Carbon, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Enzymologic, Humans, Hydroxylation, Male, Prostatic Neoplasms, Real-Time Polymerase Chain Reaction, Steroid Hydroxylases, Vitamin D3 24-Hydroxylase

ID: 145249977