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A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model

¹ University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin and ² Department of Pharmaceutical Chemistry, Wayne State University, Detroit, Michigan

Requests for reprints: Hirak S. Basu, K6/522 CSC, 600 Highland Avenue, Madison, WI 53792-5669. Phone: 608-265-4912; Fax: 608-265-8133; E-mail: hsb{at}medicine.wisc.edu.

Key Words: oxidative stress • polyamine oxidase • prostate cancer

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H₂O₂ could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression. [Cancer Res 2009;69(19):7689–95]