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Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-07-11 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01891 Yuta Naro 1 , Nicholas Ankenbruck 1 , Meryl Thomas 1 , Yaniv Tivon 1 , Colleen M. Connelly 1 , Laura Gardner 1 , Alexander Deiters 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-07-11 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01891 Yuta Naro 1 , Nicholas Ankenbruck 1 , Meryl Thomas 1 , Yaniv Tivon 1 , Colleen M. Connelly 1 , Laura Gardner 1 , Alexander Deiters 1
Affiliation
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Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure–activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines. In a chemoresistant-RCC cell line, inhibition of miR-21 via small molecule treatment rescued the expression of tumor-suppressor proteins and sensitized cells to topotecan-induced apoptosis. This resulted in a >10-fold improvement in topotecan activity in cell viability and clonogenic assays. Overall, this work reports a novel small molecule inhibitor for perturbing miR-21 function and demonstrates an approach to enhancing the potency of chemotherapeutics specifically for cancers derived from oncomir addiction.
中文翻译：
MicroRNA miR-21的小分子抑制挽救了肾细胞癌对Topotecan的化学敏感性
microRNA（miRNA）功能的化学探针是了解miRNA生物学的潜在工具，也为发现与miRNA相关的疾病的治疗方法提供了新的方法。MicroRNA-21（miR-21）是一种致癌性miRNA，在大多数癌症中均过表达，并且与驱动诸如肾细胞癌（RCC）等癌症的化学耐药性密切相关。使用基于细胞的荧光素酶报告基因检测法筛选小分子，我们确定了miR-21功能的新型抑制剂。经过结构-活性关系研究，一种优化的先导化合物证明了在几种癌细胞系中的细胞毒性。在具有化学抗性的RCC细胞系中，通过小分子处理对miR-21的抑制作用挽救了肿瘤抑制蛋白的表达，并使敏感细胞对拓扑替康诱导的细胞凋亡敏感。这导致> 在细胞活力和克隆形成测定中拓扑替康活性提高了10倍。总的来说，这项工作报告了一种新型的干扰miR-21功能的小分子抑制剂，并展示了一种增强化学疗法效力的方法，特别是针对因成瘾引起的癌症。
更新日期：2018-07-11
中文翻译：
MicroRNA miR-21的小分子抑制挽救了肾细胞癌对Topotecan的化学敏感性
microRNA（miRNA）功能的化学探针是了解miRNA生物学的潜在工具，也为发现与miRNA相关的疾病的治疗方法提供了新的方法。MicroRNA-21（miR-21）是一种致癌性miRNA，在大多数癌症中均过表达，并且与驱动诸如肾细胞癌（RCC）等癌症的化学耐药性密切相关。使用基于细胞的荧光素酶报告基因检测法筛选小分子，我们确定了miR-21功能的新型抑制剂。经过结构-活性关系研究，一种优化的先导化合物证明了在几种癌细胞系中的细胞毒性。在具有化学抗性的RCC细胞系中，通过小分子处理对miR-21的抑制作用挽救了肿瘤抑制蛋白的表达，并使敏感细胞对拓扑替康诱导的细胞凋亡敏感。这导致> 在细胞活力和克隆形成测定中拓扑替康活性提高了10倍。总的来说，这项工作报告了一种新型的干扰miR-21功能的小分子抑制剂，并展示了一种增强化学疗法效力的方法，特别是针对因成瘾引起的癌症。
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