The (+)- and (-)-gossypols potently inhibit both 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 in human and rat testes

Androgen deprivation is commonly used in the treatment of metastatic prostate cancer. The (-)-gossypol enantiomer has been demonstrated as an effective inhibitor of Bcl-2 in the treatment of prostate cancer. However, the mechanism of gossypol as an inhibitor of androgen biosynthesis is not clear. The present study compared (+)- and (-)-gossypols in the inhibition of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD)and 17 beta-HSD isoform 3 (17 beta-HSD3) in human and rat testes. Gossypol enantiomers were more potent inhibitors of rat 3 beta-HSD with IC(50)s of similar to 0.2 mu M compared to 3-5 mu M in human testes. However, human 17 beta-HSD3 was more sensitive to inhibition by gossypol enantiomers, with IC(50)s of 0.36 +/- 0.09 and 1.13 +/- 0.12 for (-)- and (+)-gossypols, respectively, compared to 3.43 +/- 0.46 and 10.93 +/- 2.27 in rat testes. were species- and enantiomer-specific differences in the sensitivity of the inhibition of 17 beta-HSD3. Gossypol enantiomers competitively inhibited both 3 beta-HSD and 17 beta-HSD3 by competing for the cofactor binding sites of these enzymes. Gossypol enantiomers, fed orally to rats (20 mg/kg), inhibited 3 beta-HSD but not 17 beta-HSD3. This finding was consistent with the in vitro data, in which rat 30-HSD was more sensitive to gossypol inhibition than rat 17 beta-HSD3. As the reverse was true for the human enzymes, gossypol might be useful for treating metastatic prostate cancer. (c) 2009 Elsevier Ltd. All rights reserved.