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Research Articles: Therapeutics, Targets, and Development

17-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response

¹ Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine; ² University of Maryland Marlene and Stewart Greenebaum Cancer Center, School of Medicine, Baltimore, Maryland

Requests for reprints: Vincent C.O. Njar, University of Maryland Baltimore, School of Medicine, 685 West Baltimore Street, HSF Room 580 I, Baltimore, MD 21201-1559. Phone: 410-706-5882; Fax: 410-706-0032. E-mail: vnjar001{at}umaryland.edu

Abstract

Inhibitors of the enzyme 17-hydroxylase/17,20 lyase are a new class of anti–prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17-hydroxylase/17,20 lyase inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI₅₀, 7.82 µmol/L and 7.55 µmol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G₁-G₀ phase arrest. Measurements of intracellular calcium levels ([Ca²⁺]_i) showed that 20 µmol/L VN/124-1 caused a release of Ca²⁺ from endoplasmic reticulum stores resulting in a sustained increase in [Ca²⁺]_i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 µmol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic. [Mol Cancer Ther 2008;7(9):2828–36]

Grant support: NIH grants R21 CA117991-01 and R01CA027440-28 awarded (V.C.O. Njar, A.M. Brodie). T.D. Gover works in the laboratory of Daniel Weinreich, which is funded by NIH grant R01NS022069-20. R.D. Bruno is supported in part by National Institute of Environmental Health Safety training grant T32 ES007263-16A1.

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.

Received 4/ 7/08; revised 6/20/08; accepted 7/ 6/08.