title: ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.
abstract: Motor neuron degeneration resulting from the aggregation of the androgen receptor with an expanded polyglutamine tract (AR-polyQ) has been linked to the development of spinal and bulbar muscular atrophy (SBMA or Kennedy disease). Here we report that adding 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators, and also increases cell survival by decreasing AR-polyQ nuclear aggregation and increasing AR-polyQ degradation in cultured cells. Intraperitoneal injection of ASC-J9 into AR-polyQ transgenic SBMA mice markedly improved disease symptoms, as seen by a reduction in muscular atrophy. Notably, unlike previous approaches in which surgical or chemical castration was used to reduce SBMA symptoms, ASC-J9 treatment ameliorated SBMA symptoms by decreasing AR-97Q aggregation and increasing VEGF164 expression with little change of serum testosterone. Moreover, mice treated with ASC-J9 retained normal sexual function and fertility. Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators.
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Yang
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Chang
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Yu
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Wu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Lu-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Shu-Shi
authors.initials: SS
authors.lastname: Chang
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003474:Curcumin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D059002:Androgen Receptor Antagonists; D003474:Curcumin; D011944:Receptors, Androgen; C471106:ASC-J9 compound