Abstract
BackgroundResistance to 5-Fluorouracil (5-FU) based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer.Materials and methodsIn 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).ResultsMimic-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.ConclusionThis 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.
Highlights
Colorectal cancer ranks third among cancer types in the United States with over 140,000 new cases each year [1]. 5-Fluorouracil (5-FU) based chemotherapy (e.g. FOLFOX) has been the major treatment option for metastatic colorectal cancer for well over 50 years [2, 3]
modified miR-129 (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. 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
Summary
Colorectal cancer ranks third among cancer types in the United States with over 140,000 new cases each year [1]. 5-Fluorouracil (5-FU) based chemotherapy (e.g. FOLFOX) has been the major treatment option for metastatic colorectal cancer for well over 50 years [2, 3]. The resistance mechanism is quite complex involving elevated target protein thymidylate synthase (TS), TP53 mutation/deletion, and DNA repair, it has been well established that resistance is due, at least in part, to the presence of highly resistant colon cancer stem cells [4, 5]. These cells, which are highly plastic in nature due to regulation by epigenetic mechanisms such as miRNA, represent an important therapeutic target [6]. Resistance to 5-Fluorouracil (5-FU) based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer
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