Development of a 5-FU Modified miR-129 Mimic as a Therapeutic for Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related deaths in the United States with non -small cell lung cancer (NSCLC) accounting for most cases. Despite advances in cancer therapeutics, the 5-year survival rate has remained poor due to several contributing factors, including its resistance to therapeutics. Therefore, there is a pressing need to develop therapeutics that can overcome resistance. Non-coding RNAs, including microRNAs (miRNAs), have been found to contribute to cancer resistance and therapeutics by modulating the expression of several targets involving multiple key mechanisms. In this study, we investigated the therapeutic potential of miR-129 modified with 5-fluorouracil (5-FU) in NSCLC. Our results show that 5-FU modified miR-129 (5-FU-miR-129) inhibits proliferation, induces apoptosis, and retains function as a miRNA in NSCLC cell lines A549 and Calu-1. Notably, we observed that 5-FU-miR-129 was able to overcome resistance to tyrosine kinase inhibitors and chemotherapy in cell lines resistant to erlotinib or 5-FU. Furthermore, we observed that the inhibitory effect of 5-FU-miR-129 can also be achieved in NSCLC cells under vehicle-free conditions. Finally, 5-FU-miR-129 inhibited NSCLC tumor growth and extended survival in vivo without toxic side effects. Altogether, our results demonstrate the potential of 5-FU-miR-129 as a highly potent cancer therapeutic in NSCLC.

Automated summary

Lung cancer is the leading cause of cancer-related deaths in the US, with resistance to therapeutics being a major factor in poor survival rates. However, a study has found that miR-129 modified with 5-FU can inhibit proliferation and induce apoptosis in NSCLC cell lines, even in those resistant to erlotinib or 5-FU. In animal experiments, 5-FU-miR-129 inhibited tumor growth and improved survival without toxic side effects.