Drug Repositioning of the α1-Adrenergic Receptor Antagonist Naftopidil: A Potential New Anti-Cancer Drug?

Abstract

Failure of conventional treatments is often observed in cancer management and this requires the development of alternative therapeutic strategies. However, new drug development is known to be a high-failure process because of the possibility of a lower efficacy than expected for the drug or appearance of non-manageable side effects. Another way to find alternative therapeutic drugs consists in identifying new applications for drugs already approved for a particular disease: a concept named “drug repurposing”. In this context, several studies demonstrated the potential anti-tumour activity exerted by α1-adrenergic receptor antagonists and notably renewed interest for naftopidil as an anti-cancer drug. Naftopidil is used for benign prostatic hyperplasia management in Japan and a retrospective study brought out a reduced incidence of prostate cancer in patients that had been prescribed this drug. Further studies showed that naftopidil exerted anti-proliferative and cytotoxic effects on prostate cancer as well as several other cancer types in vitro, as well as ex vivo and in vivo. Moreover, naftopidil was demonstrated to modulate the expression of Bcl-2 family pro-apoptotic members which could be used to sensitise cancer cells to targeting therapies and to overcome resistance of cancer cells to apoptosis. For most of these anti-cancer effects, the molecular pathway is either not fully deciphered or shown to involve α1-adrenergic receptor-independent pathway, suggesting off target transduction signals. In order to improve its efficacy, naftopidil analogues were designed and shown to be effective in several studies. Thereby, naftopidil appears to display anti-cancer properties on different cancer types and could be considered as a candidate for drug repurposing although its anti-cancerous activities need to be studied more deeply in prospective randomized clinical trials.

Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments

“…The VEGF-induced angiogenesis is inhibited by an α-blocker, doxazosin, in human umbilical vein endothelial cells (Keledjian et al, 2005). Another selective α1-blocker, naftopidil, presents with antiproliferative and cytotoxic effects on prostate cancer as well as several other cancer types in vitro, ex vivo, and in vivo (Florent et al, 2020).…”

Flubendazole suppresses VEGF‐induced angiogenesis in HUVECs and exerts antitumor effects in PC‐3 cells

“…In recent years, drug repositioning has made certain progress in the research of anti‐cancer drug discovery (Florent et al., 2020). Compared to traditional de novo drug discovery, drug repositioning has omitted long‐term in vivo and in vitro experiments, a large number of toxicological studies, and early clinical studies.…”

Neurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer

“…Sympathoadrenal system signaling mediated via the β 2 subtype of adrenergic receptors plays a central role in processes related to cancer development and progression [ 2 , 6 ]. However, it is necessary to note that activation of other subtypes of α and β adrenergic receptors might also affect cancer [ 7 , 8 , 9 , 10 , 11 , 12 ]. Epinephrine and norepinephrine might affect cancer initiation and progression via activation of one or more of the intracytoplasmic signaling cascades implicated in cancer, such as Ras/MAPK, PI3K/Akt, and JAK/STAT [ 2 , 13 ].…”