related to its off-target effects. Interestingly, naftopidil strongly inhibits the prolifer-

ation of normal prostatic fibroblasts compared with that of PCa cells and decreases

the secretion of the tumorigenic soluble factor interleukin-6 derived from normal

prostatic fibroblasts, implying that stromal support of PCa cells may be suppressed

by naftopidil in the tumor microenvironment. Importantly, no antiproliferative

effects were observed following tamsulosin treatment in PCa cells or normal pros-

tatic fibroblasts.

Similar to the results in PCa cells and normal prostatic fibroblasts, Iwamoto et al.

demonstrated that naftopidil inhibits RCC cell and vascular endothelial cell prolifer-

ation via promotion of G1 cell cycle arrest (Iwamoto et al. 2013). In an in vivo RCC

xenograft model, oral administration of naftopidil was found to strongly decrease

MVD in tissues, suggesting that naftopidil may have both direct effects in cancer

cells and indirect effects in stromal cells, such as fibroblasts and vascular endothelial

cells, in the tumor microenvironment. Additionally, tamsulosin did not show any

antiproliferative effects in RCC cells or vascular endothelial cells. However,

naftopidil has been shown to inhibit the proliferation of human lung fibroblasts

Androgen-insensitive

PCa cells

Normal fibroblasts

Androgen-sensitive

PCa cells

N

O

N

O

O H

Naftopidil

Vascular

endothelial cells

CAFs

Smooth muscle cells

Stem cells

n.e.

n.e.

n.e.

Normal

epithelial cells

Tumor microenvironment

Prostate tissue

Fig. 8.1 Growth inhibitory effects of naftopidil in the tumor microenvironment. The tumor

microenvironment in prostate cancer (PCa) includes a number of cells, such as androgen-sensitive

PCa cells, androgen-insensitive PCa cells, normal fibroblasts, carcinoma-associated fibroblasts

(CAFs), and vascular endothelial cells. Our studies of drug repositioning suggested that naftopidil

may induce G1 cell cycle arrest to block highly proliferative cell growth (Kanda et al. 2008; Hori

et al. 2011; Iwamoto et al. 2013; unpublished data). n.e., not examined

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