ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.
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.
Yang
Zhiming
Z
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.
Chang
Yu-Jia
YJ
Yu
I-Chen
IC
Yeh
Shuyuan
S
Wu
Cheng-Chia
CC
Miyamoto
Hiroshi
H
Merry
Diane E
DE
Sobue
Gen
G
Chen
Lu-Min
LM
Chang
Shu-Shi
SS
Chang
Chawnshang
C
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*
D059002:Androgen Receptor Antagonists; D003474:Curcumin; D011944:Receptors, Androgen; C471106:ASC-J9 compound