Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer.
Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer.
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DOI：
10.1038/nature14406
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发表时间：
2015-07-16
期刊：
影响因子：
64.8
通讯作者：
Sharifi N
中科院分区：
文献类型：
--
作者：
Li Z;Bishop AC;Alyamani M;Garcia JA;Dreicer R;Bunch D;Liu J;Upadhyay SK;Auchus RJ;Sharifi N
前列腺癌对去势的抵抗是由于肿瘤获得了将前体类固醇转化为5α-二氢睾酮（DHT）的代谢能力，从而促进雄激素受体（AR）的信号传导和去势抵抗性前列腺癌（CRPC）的发展。肾上腺前体类固醇合成DHT或可能从胆固醇重新合成DHT对抗性至关重要，通常需要3β-羟基类固醇脱氢酶（3βHSD）、类固醇-5α-还原酶（SRD5A）和17β-羟基类固醇脱氢酶（17βHSD）同工酶的酶促反应。阿比特龙是一种甾体17α-羟化酶/17,20-裂解酶（CYP17A1）抑制剂，可以阻断这种合成过程并延长生存期。我们假设阿比特龙被一种酶转化为更活跃的Δ4-abiraterone (D4A)，该酶阻断多种类固醇生成酶并拮抗雄激素受体（AR），这为阿比特龙的临床活性提供了额外的解释。我们发现阿比特龙在小鼠和前列腺癌患者体内转化为D4A。D4A抑制DHT合成所需的CYP17A1、3βHSD和SRD5A。此外，D4A的竞争性AR拮抗作用与强效拮抗剂恩杂鲁胺相当。D4A对异种移植物肿瘤的抗肿瘤活性也比阿比特龙强。我们的发现为阿比特龙延长生存期提供了另一种解释——转化为一种更活跃的药物。我们建议直接使用D4A治疗比阿比特龙治疗更有效。
Prostate cancer resistance to castration occurs because tumors acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signaling by the androgen receptor (AR) and the development of castration-resistant prostate cancer (CRPC). Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly require enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Δ4-abiraterone (D4A) that blocks multiple steroidogenic enzymes and antagonizes the androgen receptor (AR), providing an additional explanation for abiraterone’s clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive AR antagonism by D4A is comparable to the potent antagonist, enzalutamide. D4A also has more potent antitumor activity against xenograft tumors than abiraterone. Our findings suggest an additional explanation – conversion to a more active agent – for abiraterone’s survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.