DU145型
雄激素受体
LNCaP公司
前列腺癌
癌症研究
细胞凋亡
体内
恩扎鲁胺
生存素
医学
流浪汉
生物
化学
癌症
内科学
生物技术
生物化学
作者
Andrew K. Kwegyir-Afful,Senthilmurugan Ramalingam,Puranik Purushottamachar,Vidya P. Ramamurthy,Vincent C.O. Njar
出处
期刊:Oncotarget
[Impact Journals, LLC]
日期:2015-07-14
卷期号:6 (29): 27440-27460
被引量:89
标识
DOI:10.18632/oncotarget.4578
摘要
Galeterone (Gal) is a first-in-class multi-target oral small molecule that will soon enter pivotal phase III clinical trials in castration resistant prostate cancer (CRPC) patients. Gal disrupts androgen receptor (AR) signaling via inhibition of CYP17, AR antagonism and AR degradation. Resistance to current therapy is attributed to up-regulation of full-length AR (fAR), splice variants AR (AR-Vs) and AR mutations. The effects of gal and VNPT55 were analyzed on f-AR and AR-Vs (AR-V7/ARv567es) in LNCaP, CWR22Rv1 and DU145 (transfected with AR-Vs) human PC cells in vitro and CRPC tumor xenografts. Galeterone/VNPT55 decreased fAR/AR-V7 mRNA levels and implicates Mdm2/CHIP enhanced ubiquitination of posttranslational modified receptors, targeting them for proteasomal degradation. Gal and VNPT55 also induced significant apoptosis in PC cells via increased Bax/Bcl2 ratio, cytochrome-c release with concomitant cleavage of caspase 3 and PARP. More importantly, gal and VNPT55 exhibited strong in vivo anti-CRPC activities, with no apparent host toxicities. This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both fAR and AR-Vs. Importantly, the preclinical activity profiles, including profound apoptotic induction and inhibition of CRPC xenografts suggest that these agents offer considerable promise as new therapeutics for patients with CRPC and those resistant to current therapy.
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