title: Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms--action of two new agents.
abstract: 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 (E(2)) and E(2)/T+DHT ratio. SERMs, especially BP, reduced epithelial cell height drastically without significantly altering steroid hormone levels and E(2)/T+DHT ratio. Combination treatment reduced both acinar diameter and epithelial cell height with modest increase in E(2), T and E(2)/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.
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Lucknow 226001, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Kumar
authors.forename: Vikas
authors.initials: V
authors.lastname: Verma
authors.forename: Amit
authors.initials: A
authors.lastname: Sarswat
authors.forename: J P
authors.initials: JP
authors.lastname: Maikhuri
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Jain
authors.forename: V L
authors.initials: VL
authors.lastname: Sharma
authors.forename: Diwakar
authors.initials: D
authors.lastname: Dalela
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018120:Finasteride / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D058891:5-alpha Reductase Inhibitors; C410798:AR protein, human; D001578:Benzopyrans; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010880:Piperidines; D012333:RNA, Messenger; D011944:Receptors, Androgen; D020845:Selective Estrogen Receptor Modulators; D013196:Dihydrotestosterone; D013629:Tamoxifen; C066624:CDRI 85-287; C016601:afimoxifene; D013739:Testosterone; C508548:ormeloxifene; D004958:Estradiol; D018120:Finasteride; D001141:Aromatase