Zhang Jinping, Gao Meimei, Niu Ying, Sun Jiangang
Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Mol Biosci. 2022 Jul 4;9:860525. doi: 10.3389/fmolb.2022.860525. eCollection 2022.
Gastric cancer remains one of the major contributors to global cancer mortality, although there is no promising target drug in clinics. Hence, the identification of novel targeted drugs for gastric cancer is urgent. As a promising strategy for inducing ferroptosis for gastric cancer treatment, the ferroptosis inducer is a potential drug. Nevertheless, no ferroptosis inducer has entered clinics. So, our purpose was to identify a novel ferroptosis inducer for gastric cancer treatment using a drug repurposing strategy. Firstly, using a drug repurposing strategy with the aid of a commercialized compound library, HC-056456, a small molecule bioactive CatSper channel blocker, was characterized to inhibit the growth of gastric cancer line MGC-803. At the same time, this anti-proliferation effect can be blocked by ferrostatin-1, a ferroptosis inhibitor, indicating that HC-056456 is a ferroptosis inducer. Then, HC-056456 was identified to decrease GSH content via p53/SLC7A11 signaling pathway. Then Fe and lipid peroxide were accumulated when cells were exposed to HC-056456. Finally, HC-056456 was found to suppress the growth of gastric cancer cells by increasing p53 and repressing SLC7A11 but not in the presence of ferrostatin-1. In sum, we systematically elucidate that HC-056456 exerts anti-gastric cancer effect by provoking ferroptosis and , suggesting its potential role in gastric cancer treatment.
胃癌仍然是全球癌症死亡的主要原因之一，尽管临床上尚无有前景的靶向药物。因此，鉴定用于胃癌的新型靶向药物迫在眉睫。作为一种诱导铁死亡用于胃癌治疗的有前景策略，铁死亡诱导剂是一种潜在药物。然而，尚无铁死亡诱导剂进入临床。所以，我们的目的是使用药物重定位策略鉴定一种用于胃癌治疗的新型铁死亡诱导剂。首先，借助商业化化合物库采用药物重定位策略，对小分子生物活性CatSper通道阻滞剂HC-056456进行表征，发现其可抑制胃癌细胞系MGC-803的生长。同时，这种抗增殖作用可被铁死亡抑制剂ferrostatin-1阻断，表明HC-056456是一种铁死亡诱导剂。然后，确定HC-056456通过p53/SLC7A11信号通路降低谷胱甘肽（GSH）含量。当细胞暴露于HC-056456时，铁和脂质过氧化物会积累。最后，发现HC-056456通过增加p53和抑制SLC7A11来抑制胃癌细胞的生长，但在存在ferrostatin-1的情况下则不然。总之，我们系统地阐明了HC-056456通过引发铁死亡发挥抗胃癌作用，提示其在胃癌治疗中的潜在作用。
