title: Oral naftopidil suppresses human renal-cell carcinoma by inducing G(1) cell-cycle arrest in tumor and vascular endothelial cells.
abstract: Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, several targeting agents are being investigated. However, the efficacy of current regimens is generally insufficient for their toxicity and poor overall response rates. We have recently reported that naftopidil exerts growth-inhibitory effects on human prostate cancer cells. In this study, we investigated the biochemical mechanisms by which naftopidil produces growth-inhibitory and antiangiogenic effects on RCC. We first tested the effects of naftopidil on the proliferation of ACHN and Caki-2 RCC cells. Next, we set up a model simulating the tumor microenvironment, in which ACHN cells were grafted onto the renal capsule of mice. We then tested the effects of naftopidil on human umbilical vein endothelial cells' cell proliferation and Matrigel plug vascularization. Finally, to establish the antitumor activity of naftopidil on RCC, we tested the antitumor effects of naftopidil on excised tumor specimens from 20 patients with RCC that were grafted beneath the renal capsule of mice. Naftopidil showed similar in vitro growth-inhibitory effects on all cell lines. Fluorescence-activated cell sorting analysis revealed an increase in G1 cell-cycle arrest in all naftopidil-treated cell lines. In vivo tumorigenic studies showed a significant reduction of ACHN tumor weight, Ki-67 index, and microvessel density (MVD) in naftopidil-treated mice. Naftopidil attenuated neovascularization in an in vivo Matrigel plug assay. Studies in mouse xenograft models also showed a significant MVD reduction in naftopidil-treated excised human RCC. The growth-inhibitory effects of naftopidil suggest it may be a novel anticancer agent and a potential preventive option for RCC.
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Kato
authors.forename: Hideki
authors.initials: H
authors.lastname: Kanda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Arima
authors.forename: Taizo
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugimura
mesh_terms: D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009281:Naphthalenes / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000317:Adrenergic alpha-Antagonists; D009281:Naphthalenes; D010879:Piperazines; D012333:RNA, Messenger; C064357:naftopidil