Tian Kunpeng, Wei Jinrui, Wang Ru, Wei Mingming, Hou Fei, Wu Lichuan
School of Medicine, Guangxi University, Nanning, 530004, Guangxi, PR China.
Pediatrics Research Institute of Hunan Province, Hunan Children's Hospital, Changsha, 410007, Hunan, PR China.
Cell Death Discov. 2023 Aug 14;9(1):296. doi: 10.1038/s41420-023-01597-6.
Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.
肝癌是最致命的恶性肿瘤之一，每年死亡病例超过83万例。尽管靶向治疗药物已取得一定的临床疗效，但目前仅有索拉非尼和仑伐替尼作为一线靶向药物用于治疗晚期肝癌患者。因此，迫切需要研发更多药物。铁死亡是一种铁依赖性程序性细胞死亡（PCD），不同于包括凋亡、坏死和自噬在内的已知PCD。靶向铁死亡被认为是一种有前景的肝癌潜在治疗方式。激活转录因子3（ATF3）是一种重要的铁死亡诱导剂，靶向ATF3为癌症治疗提供了一种潜在手段。在本研究中，我们首次报道了一种槐定碱衍生物6j，其在体外和体内均具有良好的抗肝癌作用。化合物6j可通过促进细胞内铁、活性氧（ROS）和丙二醛的积累诱导肝癌细胞铁死亡。铁抑素-1抑制铁死亡可减轻6j诱导的铁、ROS和丙二醛的积累，并恢复细胞活力。进一步研究表明，化合物6j通过内质网应激上调ATF3的表达，RNA干扰敲低ATF3可减弱6j诱导的铁死亡和细胞增殖抑制。本研究将为铁死亡诱导剂的设计和抗肝癌药物的开发提供新的见解。
