Syrosingopine and UK5099 synergistically suppress non-small cell lung cancer by activating the integrated stress response

Non-small cell lung cancer (NSCLC) remains a major global health concern due to its poor long-term survival rates, highlighting the urgent need for new treatment approaches. This study investigated the combined therapeutic effects of syrosingopine and UK-5099 in NSCLC models. In cell-based assays, the combination of these two agents significantly inhibited NSCLC cell proliferation more effectively than either drug alone. The treatment led to cell cycle arrest and increased rates of apoptosis in cancer cells.

Animal studies further confirmed that this drug combination substantially reduced tumor growth in vivo. Mechanistic analysis revealed that the dual treatment caused mitochondrial dysfunction through the buildup of lactate and elevated oxidative stress levels. These changes activated an integrated stress response (ISR), specifically through the stimulation of heme-regulated inhibitor kinase (HRI). The suppression of tumor growth and cell proliferation by this combination was found to rely on ISR activation.

Overall, the results indicate that the co-administration of syrosingopine and UK-5099 offers a promising strategy for treating NSCLC by triggering ISR-mediated stress pathways and impairing cancer cell metabolism and survival.