Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2021 Jan;42(1):132-141. doi: 10.1038/s41401-020-0398-2. Epub 2020 May 13.
Hsp90 is a potential therapeutic target for tumor, as it maintains the stability of a variety of proteins related to tumor development and progression. Autophagy is a self-degradation process to maintain cellular homeostasis and autophagy inhibitors can suppress tumor growth. In this study, we identified DCZ5248, a triazine derivative, was a dual inhibitor of both Hsp90 and late-autophagy with potent antitumor activity against colon cancer cells in vitro and in vivo. We showed that DCZ5248 (0.1-10 μM) induced dose-dependent degradation of Hsp90 client proteins (AKT, CDK4, CDK6 and RAF-1) in HCT 116 colon cancer cells through a proteasome-dependent pathway. Meanwhile, DCZ5248 (0.3 μM) induced cytoplasmic vacuole formation, LC3 II conversion, p62 protein upregulation, and inhibited autophagy at the late stage in the colon cancer cell lines tested. We further revealed that the inhibition of autophagy was achieved by impairing lysosomal functions through induction of lysosomal acidification and attenuation of lysosomal cathepsin activity. The modulation of autophagy by DCZ5248 was independent of Hsp90 inhibition as the autophagy inhibition was not blocked by Hsp90 knockdown. Importantly, inhibition of both Hsp90 function and autophagy by DCZ5248 induced G-phase cell cycle arrest, apoptosis, and exerted potent antitumor activity against colon cancer cells both in vitro and in vivo. These findings demonstrate that DCZ5248 is a novel dual inhibitor of Hsp90 and autophagy with potential for colon cancer therapy.
热休克蛋白 90（Hsp90）是肿瘤的潜在治疗靶点，因为它维持着与肿瘤发生和发展相关的多种蛋白质的稳定性。自噬是一种维持细胞内环境稳定的自我降解过程，自噬抑制剂可以抑制肿瘤生长。在本研究中，我们鉴定出二氯[4-[4-(4-氯苯基)-1-哌嗪基]丁基]-1,3,5-三嗪（DCZ5248）是一种 Hsp90 和晚期自噬的双重抑制剂，对体外和体内结肠癌细胞具有强大的抗肿瘤活性。我们表明，DCZ5248（0.1-10μM）通过蛋白酶体依赖性途径诱导 HCT116 结肠癌细胞中 HSP90 客户蛋白（AKT、CDK4、CDK6 和 RAF-1）的剂量依赖性降解。同时，DCZ5248（0.3μM）在测试的结肠癌细胞系中诱导细胞质空泡形成、LC3 II 转化、p62 蛋白上调，并抑制晚期自噬。我们进一步揭示，自噬的抑制是通过诱导溶酶体酸化和减弱溶酶体组织蛋白酶活性来损害溶酶体功能来实现的。DCZ5248 对自噬的调节不依赖于 Hsp90 抑制，因为自噬抑制不受 Hsp90 敲低的阻断。重要的是，DCZ5248 通过抑制 Hsp90 功能和自噬诱导 G 期细胞周期停滞、凋亡，并在体外和体内对结肠癌细胞发挥强大的抗肿瘤活性。这些发现表明，DCZ5248 是一种新型的 Hsp90 和自噬双重抑制剂，具有治疗结肠癌的潜力。
