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Research Articles: Therapeutics, Targets, and Development

Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1

¹ M. D. Anderson Cancer Center, University of Texas, Houston, Texas and ² Arizona Cancer Center, University of Arizona; ³ ProlX Pharmaceuticals, Tucson, Arizona

Requests for reprints: Garth Powis, M. D. Anderson Cancer Center, University of Texas, FC-6.3044, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-3366; Fax: 713-745-1710. E-mail: gpowis{at}mdanderson.org

Abstract

We have reported previously that PX-478 (S-2-amino-3-[4'-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1 (HIF-1) within the tumor. We now report that PX-478 inhibits HIF-1 protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1 inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1 mRNA and inhibits translation as determined by ³⁵S labeling experiments and reporter assays using the 5' untranslated region of HIF-1. Moreover, to a lesser extent, PX-478 also inhibits HIF-1 deubiquitination resulting in increased levels of polyubiquitinated HIF-1. The inhibitory effect of PX-478 on HIF-1 levels is primarily due to its inhibition of translation because HIF-1 translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1 at multiple levels that together or individually may contribute to its antitumor activity against HIF-1-expressing tumors. [Mol Cancer Ther 2008;7(1):90–100]

Grant support: NIH grants CA90821, CA109552, and CA077204.

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 7/11/07; revised 10/29/07; accepted 12/ 1/07.