grafting) and PC-3 cell-derived tumors (intratibial injection) in an in vivo analysis

(Ishii et al. 2018a). Notably, additive naftopidil treatment showed synergistic effects

on DTX-dependent apoptosis in PCa cells in both in vitro and in vivo analyses.

Particularly in patients with castration-resistant PCa having bone metastases, this

combined treatment strategy can result in enhanced clinical outcomes compared with

DTX treatment alone. We suggest that a combination of G1 cell cycle arrest-inducing

naftopidil and G2/M cell cycle arrest-inducing DTX may strongly inhibit cell cycle

progression (Fig. 8.2).

8.3.3

Structure of Subtype-Selective a1-AR Antagonists With

Anticancer Effects

Among approved drugs and unapproved compounds, the five subtype-selective α1-

AR antagonists can be divided into two groups: the α1A-AR highly selective

antagonists tamsulosin, silodosin, and RS100329 and the α1D-AR highly selective

antagonists naftopidil and BMY7378. Importantly, Hori et al. demonstrated that

naftopidil and RS100329 show antiproliferative effects in PCa cells and normal

prostatic fibroblasts (Hori et al. 2011). Moreover, both naftopidil and RS100329

have a phenylpiperazine-based structure and have been shown to promote G1 cell

cycle arrest. Similarly, in small-cell lung carcinoma cells, the Ca²⁺/calmodulin-

dependent protein kinase inhibitor KN-62, which exhibits a phenylpiperazine-

based structure, also induces G1 cell cycle arrest (Williams et al. 1995, 1996).

Conversely, BMY7378, which also has a phenylpiperazine-based structure, does

not induce G1 cell cycle arrest at low concentrations (10 μM) but weakly promotes

G1 cell cycle arrest in PCa cells when used at a fivefold higher concentration (Hori

et al. 2011). Tamsulosin and silodosin, which do not have a phenylpiperazine-based

G1

phase

S

phase

G2

phase

M

phase

Naftopidil

Docetaxel

Fig. 8.2 The additive effects

of naftopidil treatment

combined with chemotherapy

for prostate cancer. Naftopidil

inhibits the proliferation of

prostate cancer (PCa) cells by

inducing G1 cell cycle arrest.

Docetaxel (DTX) induces G2/

M cell cycle arrest and

apoptosis in PCa cells by

inhibiting microtubule

depolymerization. Our studies

of drug repositioning strongly

suggested that the

combination of G1 cell cycle

arrest-inducing naftopidil and

G2/M cell cycle arrest-

inducing DTX may inhibit

cell cycle progression

116

K. Ishii et al.