Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells

BACKGROUND: Resistance to 5-Fluorouracil (5-FU) based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer. MATERIALS AND METHODS: In this study, we developed a novel miR-129 mimic with potent efficacy in eliminating resistant colon cancer stem cells both in vitro and in vivo. We integrated 5-FU into miR-129 by replacing Uracil (U) to generate 5-FU-miR-129 mimics (Mimic-1). RESULTS: Mimic-1 is a strong therapeutic candidate with a number of unique features. Mimic-1 can be delivered to cancer cells without any transfection reagents (e.g. lipids, viral vector, nanoparticles). Mimic-1 is more potent at inhibiting cell proliferation and inducing cell cycle arrest at G1 phase than native miR-129 and the other mimics tested, while retaining target specificity. Mimic-1 prevents colon cancer metastasis in vivo without toxicity. CONCLUSION: This represents a significant advancement in the development of a nontoxic and highly potent miRNA based cancer therapeutics and establishes a foundation for further developing Mimic-1 as a novel anti-cancer therapeutic for treating colorectal cancer.