Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan.
Yuta NaroNicholas AnkenbruckMeryl ThomasYaniv TivonColleen M ConnellyLaura GardnerAlexander DeitersPublished in: Journal of medicinal chemistry (2018)
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.
Keyphrases
- small molecule
- renal cell carcinoma
- induced apoptosis
- cell proliferation
- long non coding rna
- long noncoding rna
- poor prognosis
- protein protein
- endoplasmic reticulum stress
- high throughput
- signaling pathway
- oxidative stress
- single cell
- emergency department
- climate change
- cell therapy
- mesenchymal stem cells
- single molecule
- papillary thyroid
- photodynamic therapy
- living cells
- adverse drug