Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo.
Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo.
复制标题
Galeterone和VNPT55诱导AR/AR-V7的蛋白酶体降解，通过细胞色素C释放诱导明显的凋亡，并抑制了体内抑制castration抗性前列腺癌异种移植物的生长。
DOI：
10.18632/oncotarget.4578
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Njar VC
中科院分区：
文献类型：
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作者：
Kwegyir-Afful AK;Ramalingam S;Purushottamachar P;Ramamurthy VP;Njar VC
Galeterone（Gal）是一种一流的多靶点口服小分子药物，即将进入去势抵抗性前列腺癌（CRPC）患者的关键III期临床试验。Gal通过抑制CYP 17、AR拮抗作用和AR降解破坏雄激素受体（AR）信号传导。对当前疗法的抗性归因于全长AR（fAR）、剪接变体AR（AR-Vs）和AR突变的上调。分析gal和VNPT 55对体外LNCaP、CWR 22 Rv 1和DU 145（用AR-Vs转染）人PC细胞和CRPC肿瘤异种移植物中的f-AR和AR-Vs（AR-V7/ARv 567 es）的影响。Galeterone/VNPT 55降低fAR/AR-V7 mRNA水平，并暗示Mdm 2/CHIP增强翻译后修饰受体的泛素化，靶向它们进行蛋白酶体降解。Gal和VNPT 55还通过增加Bax/Bcl 2比率、细胞色素-C释放以及伴随的半胱天冬酶3和PARP的切割诱导PC细胞中的显著凋亡。更重要的是，gal和VNPT 55表现出强的体内抗CRPC活性，没有明显的宿主毒性。这项研究表明，gal和VNPT 55利用基于细胞的机制来消耗fAR和AR-Vs。重要的是，临床前活性概况，包括深刻的细胞凋亡诱导和CRPC异种移植物的抑制表明，这些药物作为CRPC患者和对当前治疗耐药的患者的新疗法提供了相当大的希望。
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.