Minoxidil may suppress androgen receptor-related functions
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Cheng-Lung Hsu1, Jai-Shin Liu1,3, An-Chi Lin1, Chih-Hsun Yang2, Wen-Hung Chung2, Wen-Guey Wu3
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
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
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.
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