Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer
Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer
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DOI：
10.1158/1535-7163.mct-14-0521
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发表时间：
2015-01-01
影响因子：
5.7
通讯作者：
Gleave, Martin E.
中科院分区：
文献类型：
--
作者：
Toren, Paul J.;Kim, Soojin;Gleave, Martin E.
VT-464是一种新型非甾体小分子CYP 17 A1抑制剂，具有17，20-裂解酶选择性。本研究评价了VT-464与阿比特龙（ABI）相比在去势抵抗性前列腺癌细胞系和Enzalutamide（ENZ）应答（C4-2）或ENZ抵抗（MR 49 C、MR 49 F）异种移植模型中的抗癌活性。在体外，雄激素受体（AR）的反式激活进行了评估probasin荧光素酶报告，而AR和AR调节基因和类固醇生成途径酶进行了评估蛋白质印迹和/或qRT-PCR。使用MR 49 F异种移植物模型来比较口服VT-464治疗与媒介物和醋酸阿比特龙（AA）的作用。使用LC-MS色谱法测量类固醇浓度。在C4-2和两种酶耐药细胞系中，VT-464与ABI相比显示出更大的AR反式激活降低。在基因和蛋白水平，VT-464抑制AR轴的程度比ABI更大。基因转录物星星、CYP 17 A1、HSD 17 B3和SRD 5A 1在ABI处理后增加，VT-464处理后增加程度更大。在体内，与媒介物相比，VT-464或AA治疗后肿瘤内雄激素水平显著较低，其中用VT-464观察到最大的降低。类似地，VT-464的肿瘤生长抑制和PSA降低趋势大于AA。最后，使用荧光素酶报告基因测定观察到VT-464的AR拮抗剂作用不依赖于CYP 17 A1抑制，并且使用AR配体结合结构域生物层干涉测量法证实了直接相互作用。这些临床前结果表明，VT-464对AR轴的抑制作用大于ABI，这可能是由于雄激素合成的上级选择性抑制和AR拮抗作用。(C)2014年AACR。
VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZresistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism. (C) 2014 AACR.