and bleomycin-induced lung fibrosis in mice (Urushiyama et al. 2019). Additionally,

naftopidil also induces G1 cell cycle arrest and decreases the mRNA expression of

COL4A1 (which encodes type IV collagen) and ACTA2 (which encodes α smooth

muscle actin) in human lung fibroblasts. These results suggested that naftopidil may

have potent therapeutic effects on the tumor stroma of PCa, including fibroblasts and

vascular endothelial cells.

Carcinoma-associated fibroblasts (CAFs) are present in the tumor microenviron-

ment of PCa and are characterized as activated fibroblasts that promote PCa cell

proliferation. In the PCa cell microenvironment, normal fibroblasts and CAFs

secrete various growth factors, cytokines, extracellular matrix proteins, and

microRNAs, which function to support PCa cell survival and proliferation in a

paracrine manner (Ishii et al. 2018b). In our laboratory, we examined the effects of

naftopidil on the proliferation of primary cultured CAFs derived from patients with

PCa. Naftopidil weakly inhibited the proliferation of primary cultured CAFs com-

pared with that of PCa cells, normal prostatic fibroblasts, and vascular endothelial

cells (unpublished data; Fig. 8.1). This result may be explained by the slower

proliferation of CAFs compared with that of other cells. Because naftopidil inhibits

cell cycle progression, highly proliferative cells may be strongly affected by

naftopidil in the tumor microenvironment of PCa. Additional work is needed to

fully elucidate the roles of naftopidil in CAFs.

Clinical studies have shown that the incidence of PCa is reduced in patients with

BPH administered with naftopidil for at least 3 months compared with that in

patients administered with tamsulosin (Yamada et al. 2013). Moreover, our DR

studies in patients with latent PCa concomitant with BPH also suggested that

naftopidil may have applications in long-term prevention by blocking progression

to clinical PCa. Thus, long-term naftopidil use for patients with BPH may have

various clinical benefits, and naftopidil may have application in the chemopreven-

tion of PCa in patients with BPH.

8.3.2

New Clinical Applications of Naftopidil in PCa Treatment

Recently, we proposed two possible clinical applications of naftopidil, i.e., in

combination treatment with radiotherapy (RT) or as a chemotherapy for PCa treat-

ment (Iwamoto et al. 2017; Ishii et al. 2018a).

Clinically, α1-AR antagonists, including naftopidil, improve outcomes in patients

with PCa and urinary morbidities related to brachytherapy (Merrick et al. 2005) and

extra beam RT (Prosnitz et al. 1999) without impairing safety. Indeed, additive

naftopidil treatment combined with RT has been shown to increase RT efficacy in

PC-3 cells by directly suppressing growth and by blocking the RT-induced expres-

sion of the antioxidant enzyme manganese superoxide dismutase (Iwamoto et al.

2017). Conversely, additive tamsulosin treatment combined with RT did not exert

these effects.

Additionally, additive naftopidil treatment combined with docetaxel (DTX) was

shown to promote DTX efficacy in LNCaP cell-derived tumors (sub-renal capsule

8

Drug Repositioning of the Phenylpiperazine Derivative Naftopidil in. . .

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