Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan

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.