Gossypol inhibits 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase: Its possible use for the treatment of prostate cancer

被引：10

作者：

Cao, Shuyan ^{[1
,2
,3
]}

Wang, Guimin ^{[3
,4
]}

Ge, Fei ^{[3
,4
]}

Li, Xiaoheng ^{[2
,3
]}

Zhu, Qiqi ^{[2
,3
]}

Ge, Ren-Shan ^{[2
,3
]}

Wang, Yunshan ^{[1
]}

机构：

[1] Shandong Univ, Jinan Cent Hosp, Cent Lab, 105 Jiefang Rd, Jinan 250013, Shandong, Peoples R China

[2] Wenzhou Med Univ, Affiliated Hosp 2, Ctr Sci Res, Wenzhou 325027, Zhejiang, Peoples R China

[3] Wenzhou Med Univ, Yuying Childrens Hosp, 109 Xueyuan West Rd, Wenzhou 325027, Zhejiang, Peoples R China

[4] Wenzhou Med Univ, Affiliated Hosp 2, Dept Anesthesiol, Wenzhou 325027, Zhejiang, Peoples R China

来源：

FITOTERAPIA | 2019年 / 133卷

基金：

中国国家自然科学基金;

关键词：

Gossypol; 5; alpha-reductase; 1; 3 alpha-hydroxysteroid dehydrogenase; Retinol dehydrogenase 2; Mode of action; (-)-GOSSYPOLS POTENTLY INHIBIT; ANDROGEN DEPRIVATION THERAPY; RAT LEYDIG-CELLS; 3-BETA-HYDROXYSTEROID DEHYDROGENASE; TESTOSTERONE; AT-101;

D O I：

10.1016/j.fitote.2018.12.024

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Gossypol is a yellow polyphenol isolated from cotton seeds. It has the antitumor activity and it is being tested to treat prostate cancer. However, its underlying mechanisms are still not well understood. The present study investigated the inhibitory effects of gossypol acetate on rat 5 alpha-reductase 1, 3 alpha-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 for androgen metabolism. Rat 5 alpha-reductase 1, 3 alpha-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 were expressed in COS-1 cells. Immature Leydig cells that contain these enzymes were isolated from 35-day-old male Sprague Dawley rats. The potency and mode of action of gossypol acetate to inhibit these enzymes in both enzyme-expressed preparations and immature Leydig cells were examined. Molecular docking study of gossypol on the crystal structure of 3 alpha-hydroxysteroid dehydrogenase was performed. Gossypol acetate inhibited 5 alpha-reductase 1 and 3 alpha-hydroxysteroid dehydrogenase with IC50 values of 3.33 +/- 0.07 and 0.52 +/- 0.06 x 10(-6) M in the expressed enzymes as well as 8.512 +/- 0.079 and 1.032 +/- 0.068 x 10(-6) M in intact rat immature Leydig cells, respectively. Gossypol acetate inhibited rat 5 alpha-reductase 1 in a noncompetitive mode and 3 alpha-hydroxysteroid dehydrogenase in a mixed mode when steroid substrates were supplied. Gossypol acetate weakly inhibited retinol dehydrogenase 2 with IC50 value over 1 x 10(-4 )M. Molecular docking analysis showed that gossypol partially bound to the steroid-binding site of the crystal structure of rat 3 alpha-hydroxysteroid dehydrogenase. Gossypol acetate is a potent inhibitor of rat 5 alpha-reductase 1 and 3 alpha-hydroxysteroid dehydrogenase, possibly inhibiting the formation of androgen in the prostate cancer cells.

引用

页码：102 / 108

页数：7

共 29 条

[1] Steroid recognition and regulation of hormone action: Crystal structure of testosterone and NADP(+) bound to 3 alpha-hydroxysteroid dihydrodiol dehydrogenase [J].