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¹ Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas; ² Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania; ³ Arizona Cancer Center; and ⁴ ProlX Pharmaceuticals, Tucson, Arizona

Requests for reprints: Garth Powis, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, FC-6.3044, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-745-3366; Fax: 713-745-1710. E-mail: gpowis{at}mdanderson.org

The cytosolic thioredoxin redox system composed of thioredoxin-1 and the NADPH-dependent thioredoxin reductase-1 reductase is an important regulator of cell growth and survival. Thioredoxin-1 is overexpressed in many human tumors where it is associated with increased cell proliferation, decreased apoptosis, and decreased patient survival. We hypothesized that thioredoxin reductase-1 provides a target to inhibit the activity of overexpressed thioredoxin-1 for the development of novel anticancer agents. We found that the naphthoquinone spiroketal fungal metabolite palmarumycin CP1 is a potent inhibitor of thioredoxin reductase-1, but attempts to exploit the activity of palmarumycin CP1 analogues as antitumor agents in vivo were hampered by their insolubility. We have therefore developed PX-916, a water-soluble prodrug of a palmarumycin CP1 analogue. PX-916 rapidly releases the parent compound at physiologic pH and in plasma but is stable at acid pH, allowing its i.v. administration. PX-916 is a potent inhibitor of purified human thioredoxin reductase-1 and of thioredoxin reductase-1 activity in cells and tumor xenografts when given to mice and inhibits the downstream targets of thioredoxin-1 signaling, hypoxia-inducible factor-1, and vascular endothelial growth factor in tumors. PX-916 showed excellent antitumor activity against several animal tumor models with some cures. Thus, the study shows that water-soluble inhibitors of thioredoxin reductase-1, such as PX-916, can block thioredoxin-1 signaling in tumors producing marked inhibition of tumor growth. [Mol Cancer Ther 2006;5(3):630–6]

Received 11/28/05; revised 12/27/05; accepted 1/18/06.