Tran Tuyen Thanh, Song Chin-Hee, Kim Kyung-Jin, Lee Keesook
School of Biological Sciences and Technology, Chonnam National University Gwangju, Korea.
Am J Cancer Res. 2020 Dec 1;10(12):4607-4623. eCollection 2020.
Increased expression levels of constitutively active androgen receptor splice variants (AR-Vs) cause alterations in AR signaling, resulting in drug resistance and failed hormone therapy among patients with advanced prostate cancers. Several available compounds targeting the androgen axis and AR signaling have not demonstrated efficacy in preventing prostate cancer recurrence. Here, we investigated whether a new agent, 6-[6-ethoxy-5-ispropoxy-3,4-dihydroisoquinolin-2[1H)-yl]-N-[6-methylpyridin-2-yl]nicotinamide (EIQPN), has the potential for treating advanced prostate cancer. EIQPN interacted with the AR-activation fragment-1 (AF-1) domain and blocked its androgen-independent activity, robustly decreased the protein levels of AR and variants in prostate cancer cells by inducing AR protein degradation, and inhibited the androgen-independent proliferation of various AR-positive prostate cancer cells. In xenograft mouse models, EIQPN blocked the tumor growth of androgen-independent prostate cancer cells. Overall, these findings indicate that EIQPN could serve as a novel therapeutic agent for advanced recurrent prostate cancers.
组成型活性雄激素受体剪接变体（AR-Vs）表达水平的升高会导致AR信号传导改变，从而导致晚期前列腺癌患者产生耐药性且激素治疗失败。几种现有的靶向雄激素轴和AR信号传导的化合物在预防前列腺癌复发方面尚未显示出疗效。在此，我们研究了一种新型药物6-[6-乙氧基-5-异丙氧基-3,4-二氢异喹啉-2[1H]-基]-N-[6-甲基吡啶-2-基]烟酰胺（EIQPN）是否具有治疗晚期前列腺癌的潜力。EIQPN与AR激活片段-1（AF-1）结构域相互作用并阻断其雄激素非依赖性活性，通过诱导AR蛋白降解显著降低前列腺癌细胞中AR及其变体的蛋白水平，并抑制各种AR阳性前列腺癌细胞的雄激素非依赖性增殖。在异种移植小鼠模型中，EIQPN可阻断雄激素非依赖性前列腺癌细胞的肿瘤生长。总体而言，这些发现表明EIQPN可作为晚期复发性前列腺癌的新型治疗药物。
