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.