Oral naftopidil suppresses human renal cell carcinoma by inducing G1 cell cycle arrest in tumor and vascular endothelial cells
Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude montre que l'administration orale du naftopidil inhibe la croissance d'un carcinome humain à cellules rénales en induisant l'arrêt du cycle cellulaire en phase G1 dans les cellules vasculaires endothéliales et les cellules tumorales
Renal-cell cancer (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 anti-angiogenic 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 vascular endothelial cells (HUVEC) cell proliferation and Matrigel plug vascularization. Finally, to establish the antitumor activity of naftopidil on RCC, we tested the anti-tumor effects of naftopidil on excised tumor specimens from 20 RCC patients that were grafted beneath the renal capsule of mice. Naftopidil showed similar in vitro growth-inhibitory effects on all cell lines. FACS 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 anti-cancer agent and a potential preventive option for RCC.