Minoxidil may suppress androgen receptor-related functions

Abstract

Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a Kd value of 2.6 μM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.

Minoxidil is a potential neuroprotective drug for paclitaxel-induced peripheral neuropathy

“…Minoxidil was first developed to act as antihypertension drug, but the people were found to have the side effect of hypertrichosis, an abnormal amount of hair growth over the body23. Previous studies reported some possible mechanisms of minoxidil to promote the hair growth: (i) minoxidil increase the hair follicle size, reduction on telogen follicles and increase the proportion of follicles in anagen24; (ii) minoxidil promotes hair growth via suppress androgen receptor-related functions25; (iii) minoxidil stimulates cell growth, delay cell senescence2026 and the stimulation of VEGF and prostaglandin synthesis27. Although, the mechanism of minoxidil action on hair growth is still unclear, it became a common medication for alopecia treatment.…”

Characterization of a novel androgen receptor (AR) coregulator RIPK1 and related chemicals that suppress AR-mediated prostate cancer growth via peptide and chemical screening

“…We had tested the effects of 8 of these 10 candidates on AR transcriptional reporter assay and found some of these candidates could really suppress AR transcriptional activity as shown in Figure 2B . Minoxidil also presented in the top 30 candidates and had been demonstrated to suppress AR related function [ 18 ].…”

“…After incubation for 16 h, cells were treated with ethanol, 10 nM DHT, or 0.01–10 μM HWC-489 or LHJ-647 for an additional 16 h. Luciferase activity in cell lysates was determined and normalized to protein concentrations. Relative luciferase activity was calculated using the luciferase reporter assay system [ 18 ]. (A) PC-3 cells were co-transfected with 350 ng pCDNA3-flag-hAR-N (residues 1–506), 350 ng pCDNA3-hAR-C (residues 556–919), and 300 ng MMTV-Luc plasmids.…”

Amelioration of Androgenetic Alopecia by Algal Oligosaccharides Prepared by Deep-Sea Bacterium Biodegradation

“…Although minoxidil has been used for more than 30 years to treat AGA, its precise mechanism of action on hair growth remains elusive ( Messenger and Rundegren, 2004 ). Several primary mechanisms of minoxidil action are proposed: (a) minoxidil suppresses AR-mediated functions by decreasing AR transcriptional activity and reducing the expression of AR targets at the protein level ( Hsu et al, 2014 ), (b) minoxidil exerts anagen prolongation effects by activating β-catenin pathway in dermal papilla cells ( Kwack et al, 2011 ), (c) minoxidil stimulates hair follicle angiogenesis by inducing the expression of VEGF in dermal papilla cells ( Lachgar et al, 1998 ), (d) minoxidil shows a cytoprotective activity by activating prostaglandin synthase-1 ( Michelet et al, 1997 ), and (e) minoxidil increases blood flow by dilating hair follicle arteries ( Messenger and Rundegren, 2004 ). Finasteride is a DHT synthesis inhibitor, which suppresses the conversion of testosterone to DHT by binding to 5α-reductase ( Varothai and Bergfeld, 2014 ; Kelly et al, 2016 ; Adil and Godwin, 2017 ).…”