Yin Hao, Fu Xingyan, Gao Hanyu, Gao Han, Ma Yannan, Chen Xitong, Zhang Xueqi, Du Shan-Shan, Qi Yun-Kun
School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, China.
School of Stomatology, Jining Medical University, Jining, China.
Front Oncol. 2023 Jan 12;12:1028600. doi: 10.3389/fonc.2022.1028600. eCollection 2022.
Liver cancer is the third leading cause of cancer-associated mortality globally, and >830,000 patients with liver cancer undergoing treatment succumbed to the disease in 2020, which indicates the urgent need to develop a more effective anti-liver cancer drug. In our previous study, nucleus-targeting hybrid peptides obtained from the fusion of LTX-315 and the rhodamine B group possessed potent anti-adherent cancer cell activity. Hybrid peptides accumulated in the cell nucleus and damaged the nuclear membrane, resulting in the transfer of reactive oxygen species (ROS) from the cytoplasm to the nucleus and the induction of apoptosis. However, the source of the high concentration of ROS within the cytoplasm is unclear. Moreover, although our previous study demonstrated that hybrid peptides possessed potent anticancer activity against adherent cancer cells, their efficacy on liver cancer remained unexplored. The current study found that the hybrid peptide NTP-217 killed liver cancer cells after 4-h treatment with a half-maximal inhibitory concentration of 14.6-45.7 μM. NTP-217 could stably accumulate in the liver tumor tissue and markedly inhibited liver tumor growth in mice. Furthermore, NTP-217 destroyed mitochondria and induced the leakage of mitochondrial contents, resulting in the generation of a substantial quantity of ROS. Unlike the apoptosis induced by 24 h of treatment by NTP-217, 4 h of treatment caused ROS-mediated necrotic cell death. These findings suggested that short-time treatment with hybrid peptides could trigger ROS-mediated rapid necrosis in liver cancer cells, and provided a basis for the future development of hybrid peptides as anti-liver cancer agents.
肝癌是全球癌症相关死亡的第三大主要原因，2020年有超过83万名接受治疗的肝癌患者死于该疾病，这表明迫切需要开发一种更有效的抗肝癌药物。在我们之前的研究中，由LTX-315与罗丹明B基团融合得到的细胞核靶向杂合肽具有强大的抗粘附癌细胞活性。杂合肽在细胞核中积累并破坏核膜，导致活性氧（ROS）从细胞质转移到细胞核并诱导细胞凋亡。然而，细胞质中高浓度ROS的来源尚不清楚。此外，尽管我们之前的研究表明杂合肽对粘附癌细胞具有强大的抗癌活性，但其对肝癌的疗效仍未得到探索。当前研究发现，杂合肽NTP-217在半最大抑制浓度为14.6 - 45.7μM的情况下处理4小时后可杀死肝癌细胞。NTP-217可稳定地在肝肿瘤组织中积累，并显著抑制小鼠肝肿瘤生长。此外，NTP-217破坏线粒体并诱导线粒体内容物泄漏，导致大量ROS的产生。与NTP-217处理24小时诱导的细胞凋亡不同，处理4小时会导致ROS介导的坏死性细胞死亡。这些发现表明，用杂合肽进行短时间处理可触发肝癌细胞中ROS介导的快速坏死，并为未来将杂合肽开发为抗肝癌药物提供了依据。
