title: 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 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.
authors.affiliation: Division of Hematology-Oncology, Departments of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, ROC.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Hsu
authors.forename: Jai-Shin
authors.initials: JS
authors.lastname: Liu
authors.forename: An-Chi
authors.initials: AC
authors.lastname: Lin
authors.forename: Chih-Hsun
authors.initials: CH
authors.lastname: Yang
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
authors.affiliation: Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan, ROC.
authors.forename: Wen-Guey
authors.initials: WG
authors.lastname: Wu
mesh_terms: D000959:Antihypertensive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D008914:Minoxidil / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: C410798:AR protein, human; D000959:Antihypertensive Agents; D011944:Receptors, Androgen; D008914:Minoxidil
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