structure, did not induce G1 cell cycle arrest. These reports led us to hypothesize that

α1-AR antagonists with a phenylpiperazine-based structure may suppress the prolif-

eration of cancer cells and stromal cells by inducing G1 cell cycle arrest.

In studies evaluating the mechanisms of growth inhibition by phenylpiperazine

derivatives, including naftopidil, Ishii and Sugimura demonstrated that naftopidil

can bind directly to tubulins and that three phenylpiperazine derivatives, i.e.,

naftopidil, RS100329, and BMY7378, inhibit the polymerization of tubulin; indeed,

the

phenylpiperazine-based

structure

of

these

derivatives

shows

tubulin

polymerization-inhibitory activity (Ishii and Sugimura 2015). These findings sug-

gest that the chemical structures of α1-AR antagonists contribute to differences in the

growth inhibitory mechanisms of these compounds.

In a comparison of the growth inhibitory effects of the three phenylpiperazine

derivatives, researchers have shown that the characteristics of the compound

strongly depend on the substituent group. Our studies of DR suggest that the existing

tubulin-binding drug naftopidil may exert a broad-spectrum cellular cytotoxicity in

various cell types. For example, naftopidil inhibits the proliferation of cancer cells,

such as PCa cells, RCC cells, and colon adenocarcinoma cells, as well as stromal

cells, such as fibroblasts, CAFs, and vascular endothelial cells. Therefore, modifica-

tion of the substituent group on naftopidil may facilitate the design and synthesis of

novel tubulin-binding drugs.

After we reported that the phenylpiperazine derivative naftopidil could act as a

tubulin-binding drug (Ishii and Sugimura 2015), several groups designed and

synthesized new phenylpiperazine derivatives having antiproliferative effects (Guo

et al. 2015; Prinz et al. 2017; Demirci et al. 2019). Particularly, Prinz et al. focused

on the phenylpiperazine-based structure and developed a new tubulin polymeriza-

tion inhibitor (Prinz et al. 2017). Thus, developing potent naftopidil-based anticancer

drugs without compromising safety in patients with PCa is possible.

8.4

Concluding Remarks

Clinically, naftopidil has high tolerability with fewer side effects in patients with

BPH. Our studies of DR imply that naftopidil-inhibited cell cycle progression may

block the progression of latent PCa concomitant with BPH to clinical PCa. We

believe that long-term orally active naftopidil may have clinical benefits in patients

with BPH as a chemopreventive agent for PCa during BPH treatment.

Acknowledgments We would like to thank Drs. Hideki Kanda, Yasuhide Hori, and Yoichi

Iwamoto for their assistance during the experiments and Mrs. Izumi Matsuoka and Ms. Yumi

Yoshikawa for the technical support.

8

Drug Repositioning of the Phenylpiperazine Derivative Naftopidil in. . .

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