Erschienen in:
01.04.2012 | PRECLINICAL STUDIES
Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents
verfasst von:
Rajeev Kumar, Vikas Verma, Amit Sarswat, J. P. Maikhuri, Ashish Jain, Rajeev K. Jain, V. L. Sharma, Diwakar Dalela, Gopal Gupta
Erschienen in:
Investigational New Drugs
|
Ausgabe 2/2012
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Summary
The existing drugs for benign prostatic hyperplasia (BPH) are partially effective with undesirable side-effects; hence new agents acting by different mechanism(s) are required as supplements. Modulation of estrogen receptor signaling using selective estrogen receptor modulators (SERMs) offers an alternative approach for BPH management. Using human BPH-derived stromal cells and tissue explants in culture we evaluated two SERMs, DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2 H-1-benzopyran (BP) and Ormeloxifene (Orm) in comparison to Tamoxifen (Tam) and 4-hydroxytamoxifen (OHT). BP, OHT and Tam were more effective than Orm in reducing stromal cell proliferation of human BPH. BP was either equipotent or more effective than OHT and Tam in increasing estrogen receptor(ER)-ß, TGFß1, Fas and FasL, and in decreasing ER-α, AR, EGF-R and IGF-I expressions in BPH stromal cells. BP, Tam and Orm (1.0 mg/Kg) reduced rat prostate weights by almost same extent as Finasteride (Fin, 5.0 mg/Kg); however combination treatment (SERM+Fin) was more effective. BP was exceptionally efficient in reducing IGF-1 and cleaving PARP while combination treatments more effectively increased bax:bcl-2 ratio. Fin reduced acinar diameter and prostatic DHT level but increased testosterone, estradiol (E2) and E2/T+DHT ratio. SERMs, especially BP, reduced epithelial cell height drastically without significantly altering steroid hormone levels and E2/T+DHT ratio. Combination treatment reduced both acinar diameter and epithelial cell height with modest increase in E2, T and E2/T+DHT. The study reveals the potential of SERMs per se for BPH management, and more effectively in combination with a 5α-reductase inhibitor. BP appears promising for further evaluation as a drug candidate for BPH and prostate cancer.