Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou, Zhejiang Province, China.
Scand J Gastroenterol. 2024 Jun;59(6):730-736. doi: 10.1080/00365521.2024.2315317. Epub 2024 Mar 1.
Hepatocellular carcinoma (HCC) is the most malignant cancer worldwide. Sorafenib (SRF) is a common therapeutic drug used for patients with advanced HCC. Nevertheless, drug resistance frequently occurs in patients treated with sorafenib. Glycyrrhizic acid (GRA) is a natural compound that is identified to exhibit anti-cancer effects. In this work, we aimed to investigate the effects of GRA on SRF-resistant HCC cells and the potential regulatory mechanisms.
We established SRF-resistant HCC cell lines and administrated GRA treatment. We performed CCK-8 and colony formation experiments to detect cell proliferation. The accumulation of lipid reactive oxygen species (ROS) and iron levels were measured to evaluate ferroptosis. The protein levels of ferroptosis suppressor glutathione peroxidase 4 (GPX4) and SLC7A11, and the activation of AKT and mTOR were measured with western blotting assay.
GRA treatment notably suppressed the viability and proliferation of SRF-resistant HCC cells. SRF-resistant HCC cells exhibited repressed ferroptosis level activated AKT/mTOR cascade, and GRA treatment reversed these effects. Inhibition of ferroptosis and activation of mTOR reversed the anti-proliferation effects of GRA on SRF-resistant HCC cells.
Treatment with GRA could effectively reverse the SRF resistance of HCC cells inducing ferroptosis and inactivating the AKT/mTOR cascade.
肝细胞癌（HCC）是全球最恶性的癌症。索拉非尼（SRF）是一种常用于治疗晚期 HCC 患者的常用治疗药物。然而，接受索拉非尼治疗的患者经常会出现耐药性。甘草酸（GRA）是一种天然化合物，被认为具有抗癌作用。在这项工作中，我们旨在研究 GRA 对 SRF 耐药 HCC 细胞的影响及其潜在的调节机制。
我们建立了 SRF 耐药 HCC 细胞系并给予 GRA 处理。我们进行了 CCK-8 和集落形成实验来检测细胞增殖。测量脂质活性氧（ROS）和铁水平的积累来评估铁死亡。用 Western blot 检测铁死亡抑制剂谷胱甘肽过氧化物酶 4（GPX4）和 SLC7A11 的蛋白水平以及 AKT 和 mTOR 的激活。
GRA 处理显著抑制了 SRF 耐药 HCC 细胞的活力和增殖。SRF 耐药 HCC 细胞表现出抑制的铁死亡水平，激活 AKT/mTOR 级联，而 GRA 处理逆转了这些效应。抑制铁死亡和激活 mTOR 逆转了 GRA 对 SRF 耐药 HCC 细胞的抗增殖作用。
用 GRA 治疗可有效逆转 HCC 细胞的 SRF 耐药性，诱导铁死亡并失活 AKT/mTOR 级联。
