Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics

Yuen, John G; Fesler, Andrew; Hwang, Ga‐Ram; Chen, Lan-Bo; Ju, Jingfang

doi:10.1016/j.ymthe.2022.07.015

Cited by 6 publications

(8 citation statements)

References 81 publications

(103 reference statements)

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“…This is consistent with our previous studies that have shown that 5-FU-modified miRNAs can be delivered without the use of a transfection vehicle in pancreatic, gastric, lung, and breast cancer. 46–49 In addition, this is consistent with previous studies that show that 5-FU-miR-129, specifically, inhibits proliferation in CRC via vehicle-free delivery. 34 Notably, 5-FU is not listed among the list of current treatments for patients with NSCLC.…”

Section: Discussionsupporting

confidence: 91%

“…This is highly consistent with our recent findings that 5-FU-modified miRNAs can serve as a platform miRNA-based therapeutic technology in several different cancer types, including the therapeutic potential of 5-FU-miR-129 in CRC. 34,46–49 As seen by its ability to inhibit proliferation and induce apoptosis in NSCLC cell lines A549 and Calu-1 (Figure 1), our results demonstrate 5-FU-miR-129’s potential in NSCLC.…”

Section: Discussionsupporting

confidence: 62%

“…Currently, the development and refinement of oligonucleotide delivery has been an area of study in RNA-based therapeutics. 46,69 The inherent toxicity and unforeseen side effects of some delivery vehicles have been an obstacle in the effective delivery of RNA-based therapeutics. 46,70,71 Our results demonstrate that 5-FU-miR-129 can be delivered to NSCLC cell without the aid of a delivery vehicle via knock down of Bcl-2 and HMGB1 expression and inhibition of proliferation (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…46,69 The inherent toxicity and unforeseen side effects of some delivery vehicles have been an obstacle in the effective delivery of RNA-based therapeutics. 46,70,71 Our results demonstrate that 5-FU-miR-129 can be delivered to NSCLC cell without the aid of a delivery vehicle via knock down of Bcl-2 and HMGB1 expression and inhibition of proliferation (Figure 4). This is consistent with our previous studies that have shown that 5-FU-modified miRNAs can be delivered without the use of a transfection vehicle in pancreatic, gastric, lung, and breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Cell lines were transfected with Oligofectamine™ (Thermo Fisher Scientific, Waltham, MA, USA) and oligonucelotides as previously described. 34,46 In brief, A549, Calu-1, A549 (5-FU), and HCC827ER cell lines were seeded onto 6-well plates at a cell density of 1 × 10 5 cells/well. 24 hours later, cells were transfected with Oligofectamine™ and their respective oligonucleotides according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

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

Hwang

Yuen

Fesler³

et al. 2022

Preprint

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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.

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Section: Discussionsupporting

confidence: 91%