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Research Articles: Therapeutics, Targets, and Development

Antineoplastic agents target the 25-hydroxyvitamin D₃ 24-hydroxylase messenger RNA for degradation: implications in anticancer activity

¹ Department of Immunopathology, Children, Youth, and Women's Health Service, ² Department of Pediatrics and ³ School of Molecular and Biomedical Science, University of Adelaide, ⁴ Hanson Institute, and ⁵ School of Pharmaceutical, Molecular, and Biomedical Sciences, University of South Australia, Adelaide, Australia

Requests for reprints: Charles S. Hii, Department of Immunopathology, Women's and Children's Hospital, 72 King William Road, Adelaide 5006, Australia. Phone: 61-88161-6078; Fax: 61-88161-6046. E-mail: charles.hii{at}adelaide.edu.au

Abstract

Calcitriol or 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] has antitumor activity and hence its levels in patients may play an important role in disease outcome. Here, we report that the antineoplastic agents, daunorubicin hydrochloride, etoposide, and vincristine sulfate inhibited the ability of 1,25(OH)₂D₃ to cause the accumulation of mRNA for kidney 25-hydroxyvitamin D₃ 24-hydroxylase (CYP24), an enzyme which catabolizes this hormone. This was not due to a drug-induced cytotoxic effect, reduction in the expression of the vitamin D receptor or inhibition of the vitamin D receptor–mediated activation of the mitogen-activated protein kinases or CYP24 promoter activity. Interestingly, there was selective degradation of CYP24 mRNA in the presence of the drugs. This was accompanied by an enhancement in the levels of 1,25(OH)₂D₃ in cells incubated with 25-hydroxy vitamin D₃. These data identify a novel mechanism of action of some commonly used antineoplastic agents which by decreasing the stability of CYP24 mRNA would prolong the bioavailability of 1,25(OH)₂D₃ for anticancer actions. [Mol Cancer Ther 2007;6(12):3131–8]

Grant support: Women's and Children's Hospital Research Foundation (C. Hii and B. May), the Australian Research Council (B. May and C. Hii), and the National Health and Medical Research Council of Australia (A. Ferrante and C. Hii).

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.

⁸ J. Tan, P. Anderson, and C. Hii, unpublished data.

Received 6/25/07; revised 9/14/07; accepted 10/24/07.