Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China.
Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
Cell Death Dis. 2024 Jun 19;15(6):431. doi: 10.1038/s41419-024-06821-4.
Non-small cell lung cancer (NSCLC) presents a global health challenge due to its low five-year survival rates, underscoring the need for novel therapeutic strategies. Our research explored the synergistic mechanisms of syrosingopine and UK-5099 in treating NSCLC. In vitro experiments showed that the combination of syrosingopine and UK-5099 significantly synergized to suppress NSCLC proliferation. Further experiments revealed that this combination induced cell cycle arrest and promoted apoptosis in NSCLC cells. In vivo experiments demonstrated that the combination of syrosingopine and UK-5099 markedly inhibited tumor growth. Mechanistic studies revealed that this drug combination promoted mitochondrial damage by inducing lactate accumulation and oxidative stress. Additionally, the combination triggered an integrated stress response (ISR) through the activation of heme-regulated inhibitor kinase (HRI). Importantly, our findings suggested that the synergistic suppression of NSCLC by syrosingopine and UK-5099 was dependent on ISR activation. In summary, our study proposed a promising therapeutic approach that involved the combination of Syrosingopine and UK-5099 to activate ISR, significantly hindering NSCLC growth and proliferation.
非小细胞肺癌（NSCLC）由于其五年生存率低，是一个全球性的健康挑战，这凸显了需要新的治疗策略。我们的研究探索了辛酸钠和 UK-5099 联合治疗 NSCLC 的协同机制。体外实验表明，辛酸钠和 UK-5099 的联合显著协同抑制 NSCLC 的增殖。进一步的实验表明，这种联合诱导 NSCLC 细胞的细胞周期停滞和促进细胞凋亡。体内实验表明，辛酸钠和 UK-5099 的联合显著抑制肿瘤生长。机制研究表明，这种药物联合通过诱导乳酸积累和氧化应激来促进线粒体损伤。此外，该联合通过激活血红素调节抑制剂激酶（HRI）触发整合应激反应（ISR）。重要的是，我们的研究结果表明，辛酸钠和 UK-5099 对 NSCLC 的协同抑制作用依赖于 ISR 的激活。总之，我们的研究提出了一种有前途的治疗方法，涉及辛酸钠和 UK-5099 的联合使用以激活 ISR，显著抑制 NSCLC 的生长和增殖。
