Evaluation of 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 as a therapeutic agent for androgen-dependent prostate cancer.

Abstract

The high incidence of prostate cancer and lack of an effective, long-term treatment for metastatic disease highlights the need for more potent non-calcemic vitamin D analogs as potential alternative or combinational prostate cancer therapies. Among the analogs, 19-nor-1alpha,25-dihydroxyvitamin D2 (19-nor-1alpha,25(OH)2D2) known as paricalcitol or Zempler, has less calcemic effects and an equipotential activity as 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) in several in vivo and in vitro systems. It was recently demonstrated that a modified analog of paricalcitol, 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 (MART-10) compared to 1alpha,25(OH)2D3 was more effective in inhibiting proliferation of an immortalized normal prostate cell line (PZ-HPV-7) (1,000-fold) and invasion of PC-3 prostate cancer cells (10-fold). In this study, the effects of MART-10 and 1alpha,25(OH)2D3 on proliferation, vitamin D receptor transactivation, vitamin D-binding protein (DBP) binding, CYP24A1 (24-OHase) substrate hydroxylation kinetics, and induction of CYP24A1 gene expression were compared in an androgen-dependent prostate cancer cell model, LNCaP. The results demonstrated that MART-10 was 1,000-fold more active than 1alpha,25(OH)2D3 in inhibiting LNCaP cell proliferation. MART-10 was more active than 1alpha,25(OH)2D3 in up-regulating a vitamin D receptor-responsive Luciferase construct and inducing CYP24A1 gene expression in LNCaP prostate cancer cells. In addition, MART-10 has a lower affinity for DBP and less substrate degradation by CYP24A1 compared to 1alpha,25(OH)2D3, indicating that MART-10 has more bioavailability and a longer half-life. Thus, these data suggest that MART-10 may be a potential candidate as a therapeutic agent for prostate cancer, especially for patients who fail in conventional therapies.

• Authors: John N Flanagan, Shasha Zheng, Kun-Chun Chiang, Atsushi Kittaka, Toshiyuki Sakaki, Sachie Nakabayashi, Xiansi Zhao, Remco A Spanjaard, Kelly S Persons, Jeffrey S Mathieu, Michael F Holick, Tai C Chen
• Journal: Anticancer research (Anticancer Res) Vol. 29 Issue 9 Pg. 3547-53 (Sep 2009) ISSN: 1791-7530 [Electronic] Greece
• PMID: 19667147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-hydroxypropyl-1,25-dihydroxyvitamin D3
• Androgens
• DNA Primers
• RNA, Messenger
• Cholecalciferol
• Steroid Hydroxylases
• CYP24A1 protein, human
• Vitamin D3 24-Hydroxylase

Topics

• Androgens (physiology)
• Base Sequence
• Cell Line, Tumor
• Cholecalciferol (analogs & derivatives, therapeutic use)
• DNA Primers
• Humans
• Male
• Neoplasms, Hormone-Dependent (drug therapy, pathology)
• Polymerase Chain Reaction
• Prostatic Neoplasms (drug therapy, pathology)
• RNA, Messenger (genetics)
• Steroid Hydroxylases (genetics)
• Vitamin D3 24-Hydroxylase