(Masuda et al. 2020). Based on epidemiological evidence, quinazoline-based, sub-

type-nonselective α1-AR antagonists, such as doxazosin, prazosin, and terazosin,

have been extensively investigated and have been shown to have growth inhibitory

effects in PCa cells (Kyprianou 2000). In PCa cells, the growth inhibitory effects of

quinazoline-based, subtype-nonselective α1-AR antagonists have been shown to be

involved with apoptosis induction (Kyprianou and Benning 2000; Lin et al. 2007).

Kyprianou et al. evaluated the structures of quinazoline-based compounds and

reported that quinazoline-based, subtype-nonselective α1-AR antagonist-induced

apoptosis may be independent of the α1-AR signal and biological characteristics of

PCa cells (Anglin et al. 2002; Benning and Kyprianou 2002). Additionally, Garrison

et al. reported that doxazosin and the novel lead quinazoline-derived compound

DZ-50 reduced the viability of vascular endothelial cells, leading to the suppression

of tumor vascularity in PCa xenografts (Garrison et al. 2007). Although doxazosin

and DZ-50 have quinazoline-based structures, these effects in vascular endothelial

cells may not involve an apoptotic mechanism. Notably, several studies

demonstrated that the subtype-selective α1-AR antagonist tamsulosin has no growth

inhibitory effects in PCa cells (Kyprianou and Benning 2000; Benning and

Kyprianou 2002).

8.3

Important Observations

8.3.1

Anticancer Effects of Naftopidil in PCa Treatment

In DR studies from our laboratory, we demonstrated that naftopidil has growth

inhibitory effects by inducing G1 cell cycle arrest in PCa cells, renal cell carcinoma

(RCC) cells, and colon adenocarcinoma cells, as well as in normal prostatic

fibroblasts and vascular endothelial cells (Kanda et al. 2008; Hori et al. 2011;

Iwamoto et al. 2013; Ishii and Sugimura 2015) (Fig. 8.1).

In PCa cells, naftopidil inhibits cell proliferation in human LNCaP cells, which

are androgen sensitive and androgen receptor positive, as well as human PC-3 cells,

which are androgen insensitive and androgen receptor negative, in a concentration-

dependent manner (Kanda et al. 2008). The antiproliferative mechanisms of

naftopidil involve the induction of G1 cell cycle arrest linked to increased expression

of p27 and p21 in LNCaP cells and p21 in PC-3 cells as well as the inhibition of

AKT phosphorylation at Ser473, particularly in PC-3 cells. In vivo analyses have

shown that oral administration of naftopidil suppresses PC-3 tumor growth by

reducing microvessel density (MVD). Additionally, naftopidil-induced apoptosis

was not detected by Hoechst 33258 staining, DNA ladder formation, or poly-

(ADP ribose) polymerase cleavage.

Additionally, Hori et al. demonstrated that naftopidil exerts antiproliferative

effects, which are independent of α1-AR subtype (α1A, α1B, and α1D) expression in

PCa cells and normal prostatic fibroblasts; these findings supported that naftopidil is

likely to promote G1 cell cycle arrest in several types of cells (Hori et al. 2011).

Accordingly, we hypothesized that the antiproliferative effects of naftopidil may be

8

Drug Repositioning of the Phenylpiperazine Derivative Naftopidil in. . .

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