Minoxidil may suppress androgen receptor-related functions

// Cheng-Lung Hsu 1 , Jai-Shin Liu 1,3 , An-Chi Lin 1 , Chih-Hsun Yang 2 , Wen-Hung Chung 2 , Wen-Guey Wu 3 1 Division of Hematology-Oncology, Departments of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC; 2 Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC; 3 Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan, ROC Correspondence: Cheng-Lung Hsu, email: // Wen-Guey Wu, email: // Keywords : minoxidil, androgen, androgen receptor, androgenetic alopecia, prostate cancer Received : February 10, 2014 Accepted : April 07, 2014 Published : April 08, 2014 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 K d 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.