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Research Articles: Therapeutics, Targets, and Development

QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D₃, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells

¹ Department of Surgery, Dartmouth Medical School, Lebanon, New Hampshire; ² Department of Chemistry, Johns Hopkins University, Baltimore, Maryland; and Departments of ³ Biochemistry and ⁴ Pharmacology and Toxicology and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia

Requests for reprints: Sujatha Sundaram, Department of Surgery, Dartmouth Medical School, One Medical Center Drive, HB 7850, Lebanon, NH 03756. Phone: 603-650-5008; Fax: 603-650-4928. E-mail: Sujatha.Sundaram{at}dartmouth.edu

Abstract

The enzyme 24-hydroxylase, also known as CYP24, metabolizes 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and is an established marker of vitamin D activity. Our studies evaluated the influence of a low-calcemic 1,25(OH)₂D₃ analogue, QW-1624F2-2 (QW), on the regulation of CYP24 expression in MKL-4 cells, a metastatic mammary tumor cell model. 1,25(OH)₂D₃ and its analogue, EB 1089, stimulated CYP24 induction at both protein and transcript levels. In contrast, QW failed to produce a sustained stimulation of CYP24, due, in large part, to a reduction in the stability of the CYP24 message. QW enhanced the capacity of 1,25(OH)₂D₃ and EB 1089 to inhibit tumor cell proliferation by 2-fold. QW also blocked the sustained induction of CYP24 expression by 1,25(OH)₂D₃ and EB 1089, increased the potency of 1,25(OH)₂D₃ and EB 1089, and inhibited breast tumor cell proliferation and invasion. [Mol Cancer Ther 2006;5(11):2806–14]

Grant support: U.S. Army Medical Research and Materiel Command under contract W81XWH0410736, NIH grant CA 93547, and American Institute for Cancer Research grant 02-A068-REN.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Available at http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi.

Received 2/20/06; revised 8/29/06; accepted 9/11/06.

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