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Updated: Aug 7, 2025
Author Spotlight: Establishing a Murine Non-Small Cell Lung Cancer Model for Developing Nanoformulations of Anticancer Drugs
Published on: May 10, 2024
Development of a 5-FU modified miR-129 mimic as a therapeutic for non-small cell lung cancer
Ga-Ram Hwang1,2, John G Yuen1,3,4, Andrew Fesler5
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Abstract:
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 an 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.
Insights
A novel 5-fluorouracil (5-FU) modified microRNA-129 (miR-129) effectively targets non-small cell lung cancer (NSCLC). This 5-FU-miR-129 inhibits tumor growth and overcomes therapeutic resistance in NSCLC models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality.
- Therapeutic resistance significantly limits treatment efficacy and patient survival in NSCLC.
- Non-coding RNAs, including microRNAs, play crucial roles in cancer progression and drug resistance.
Purpose of the Study:
- To investigate the therapeutic potential of a novel 5-fluorouracil (5-FU) modified microRNA-129 (miR-129) in NSCLC.
- To evaluate the efficacy of 5-FU-miR-129 in overcoming therapeutic resistance in NSCLC models.
Main Methods:
- Synthesized 5-FU modified miR-129 (5-FU-miR-129).
- Assessed the effects of 5-FU-miR-129 on NSCLC cell proliferation, apoptosis, and miRNA function in vitro.
- Evaluated the ability of 5-FU-miR-129 to overcome resistance to erlotinib and 5-FU in resistant NSCLC cell lines.
- Tested 5-FU-miR-129 in NSCLC cells under vehicle-free conditions.
- Determined the in vivo efficacy and toxicity of 5-FU-miR-129 in a murine NSCLC xenograft model.
Main Results:
- 5-FU-miR-129 demonstrated significant inhibition of NSCLC cell proliferation and induction of apoptosis in vitro.
- The modified miRNA retained its function as an miRNA in NSCLC cell lines.
- 5-FU-miR-129 successfully overcame resistance to tyrosine kinase inhibitors and chemotherapy in resistant NSCLC cell lines.
- Effective inhibition was observed even under vehicle-free conditions, suggesting potential for simplified delivery.
- In vivo studies showed that 5-FU-miR-129 inhibited NSCLC tumor growth and extended survival without observable toxic side effects.
Conclusions:
- 5-FU-miR-129 is a potent therapeutic agent against NSCLC.
- This novel therapeutic overcomes key mechanisms of drug resistance in NSCLC.
- 5-FU-miR-129 holds significant promise as a next-generation cancer therapeutic for NSCLC treatment.
