title: Naftopidil, a selective {alpha}1-adrenoceptor antagonist, suppresses human prostate tumor growth by altering interactions between tumor cells and stroma.
abstract: In prostate cancer, tumor-stroma interactions play a critical role in the promotion of tumorigenesis, and thus the prevention of those interactions is a promising target to suppress tumor growth. Several studies demonstrated that alpha(1)-adrenoceptor (α(1)-AR) antagonists, therapeutic drugs for benign prostatic hyperplasia, have growth inhibitory effects on human prostate cancer (PCa) cells through induction of apoptosis or G(1) cell-cycle arrest. However, their direct actions on stromal cells surrounding cancer cells have not yet been elucidated. In this study, we investigated the effects of subtype-selective α(1)-AR antagonists (naftopidil, tamsulosin, and silodosin) on prostate tumor growth with a focus on the role of stroma, using commercially available fibroblast cells (PrSC). Tumorigenic studies in vivo showed significant reductions in tumor growth when E9 cells (an androgen low-sensitive LNCaP subline) grafted with PrSC were treated with naftopidil. In in vitro analyses, naftopidil and silodosin showed antiproliferative effects on PCa cells regardless of androgen sensitivity and α(1)-AR subtype expression. In PrSC, a strong growth inhibitory effect was observed with naftopidil but not silodosin. Flow cytometric analysis revealed that naftopidil, but not silodosin, induced G(1) cell-cycle arrest in both PCa cells and PrSC. In naftopidil-treated PrSC, total interleukin-6 protein was significantly reduced with increased suppression of cell proliferation. Silodosin induced weak early apoptosis only in PCa cells. These findings demonstrated that naftopidil strongly suppressed cell proliferation of stromal cells, resulting in decreased tumorigenic soluble factor, suggesting that naftopidil might be effective in preventing stromal support of tumor cells.
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hori
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Hideki
authors.initials: H
authors.lastname: Kanda
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Kohei
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Norihito
authors.initials: N
authors.lastname: Soga
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kise
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Arima
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugimura
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D015850:Interleukin-6; D009281:Naphthalenes; D010879:Piperazines; D012333:RNA, Messenger; C064357:naftopidil