Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei Province 430072, China.
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei Province 430072, China; College of Bioengineering Wuhan Polytechnic, Wuhan, Hubei 430074, China.
Eur J Pharmacol. 2018 Jun 5;828:67-79. doi: 10.1016/j.ejphar.2018.03.026. Epub 2018 Mar 19.
Gastric cancer is the second leading cause of cancer-related deaths in the world. SAHA, one of the emerging HDAC inhibitor widely used for cancer treatment, has unignorable side effects, as it is a multi-target HDAC inhibitor. However, it is believed that specifically targeting against fewer HDACs might decrease this cytoxin effect. In our previous work, we have designed and synthesized a series of new compounds, which specifically targets to HDAC6, and TC24 was one of them. In this study, we further demonstrated that TC24 selectively inhibited the activity of HDAC6 other than class I HDACs. TC24 exhibited strong anti-proliferation and anti-motility ability toward gastric cancer cells but had no obvious cytoxin effect on gastric normal GES-1 cells. The anti-cancer effect of TC24 was triggered by G2/M cell cycle arrest, apoptosis and the loss of mitochondrial membrane potential. Bcl-2, cdc 2 and cyclin B1 were decreased while Bax and cleaved-PARP were increased. Also, TC24 suppressed tumor angiogenesis via the reduction of HIF-1α and VEGF. All the above data supported that TC24 was a selective inhibitor of HDAC6 and strongly suppressed the proliferation of gastric cancer cells via inducing cell cycle arrest and cell apoptosis and tumor angiogenesis inhibition, suggesting TC24 is potentially a novel therapeutic agent for gastric cancer and the research on chemical structure of TC24 would promote the understanding of the drug design of related compounds.
胃癌是全球癌症相关死亡的第二大主要原因。SAHA 是一种新兴的组蛋白去乙酰化酶（HDAC）抑制剂，广泛用于癌症治疗，但其具有不可忽视的副作用，因为它是一种多靶点 HDAC 抑制剂。然而，人们认为针对较少的 HDACs 可能会降低这种细胞毒素作用。在我们之前的工作中，我们设计并合成了一系列新的化合物，它们专门针对 HDAC6，TC24 就是其中之一。在这项研究中，我们进一步证明 TC24 选择性地抑制了 HDAC6 的活性，而不是 I 类 HDACs。TC24 对胃癌细胞表现出强烈的增殖抑制和运动抑制作用，但对胃正常 GES-1 细胞没有明显的细胞毒素作用。TC24 的抗癌作用是通过 G2/M 细胞周期阻滞、凋亡和线粒体膜电位丧失触发的。Bcl-2、cdc2 和细胞周期蛋白 B1 减少，而 Bax 和 cleaved-PARP 增加。此外，TC24 通过减少 HIF-1α 和 VEGF 来抑制肿瘤血管生成。所有这些数据表明，TC24 是一种选择性的 HDAC6 抑制剂，通过诱导细胞周期阻滞和细胞凋亡以及抑制肿瘤血管生成，强烈抑制胃癌细胞的增殖，这表明 TC24 可能是一种新型的胃癌治疗药物，对 TC24 的化学结构研究将促进相关化合物的药物设计的理解。
