Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells.
Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells.
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DOI：
10.18632/oncotarget.22322
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发表时间：
2018-02-06
期刊：
影响因子：
--
通讯作者：
Ju J
中科院分区：
文献类型：
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作者：
Wu N;Fesler A;Liu H;Ju J
对5-氟尿嘧啶（5-FU）化疗的耐药性是晚期结直肠癌患者治疗失败的主要原因。在这项研究中，我们开发了一种新型 miR-129 模拟物，在体外和体内均能有效消除耐药性结肠癌干细胞。我们通过替换尿嘧啶 (U) 将 5-FU 整合到 miR-129 中，生成 5-FU-miR-129 模拟物 (Mimic-1)。 Mimic-1 是一种强大的治疗候选药物，具有许多独特的功能。 Mimic-1 无需任何转染试剂（例如脂质、病毒载体、纳米颗粒）即可递送至癌细胞。 Mimic-1 比天然 miR-129 和其他测试的模拟物更有效地抑制细胞增殖和诱导 G1 期细胞周期停滞，同时保留靶标特异性。 Mimic-1可在体内预防结肠癌转移，且无毒性。这代表了无毒且高效的基于 miRNA 的癌症疗法的发展取得了重大进展，并为进一步开发 Mimic-1 作为治疗结直肠癌的新型抗癌疗法奠定了基础。
Resistance to 5-Fluorouracil (5-FU) based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer. 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). 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. 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.