Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center & Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.
College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China.
J Zhejiang Univ Sci B. 2023 Mar 15;24(3):232-247. doi: 10.1631/jzus.B2200351.
Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical -(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.
细胞内活性氧（ROS）的急剧增加会诱导细胞凋亡，而大多数化疗药物会导致 ROS 的积累。在这里，我们构建了一种有机化合物，砷化 -（4-（1,3,2-二硫代亚砷烷-2-基）苯基）丙烯酰胺（AAZ2），它可以促使 ROS 触发胃癌（GC）中的线粒体依赖性细胞凋亡。从机制上讲，AAZ2 通过靶向丙酮酸脱氢酶激酶 1（PDK1），导致代谢改变和氧化还原平衡失调，随后抑制磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/雷帕霉素靶蛋白（mTOR）通路，导致 B 细胞淋巴瘤 2（Bcl2）/Bcl2 相关 X（Bax）/半胱天冬酶-9（Cas9）/半胱天冬酶-3 级联的激活。重要的是，我们的体内数据表明，AAZ2 可以抑制 GC 异种移植物的生长。总的来说，我们的数据表明，AAZ2 可以通过靶向 PDK1 导致 GC 中的代谢异常，从而引发线粒体依赖性细胞凋亡。
