A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

The onset of drug resistance is a major cause of treatment failure in multiple myeloma. Although increasing evidence is defining the role of miRNAs in mediating drug resistance, their potential activity as drug-sensitizing agents has not yet been investigated in multiple myeloma. Here we studied the...

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Bibliographic Details
Published in:Clinical cancer research 2016-03, Vol.22 (5), p.1222-1233
Main Authors: Gullà, Annamaria, Di Martino, Maria Teresa, Gallo Cantafio, Maria Eugenia, Morelli, Eugenio, Amodio, Nicola, Botta, Cirino, Pitari, Maria Rita, Lio, Santo Giovanni, Britti, Domenico, Stamato, Maria Angelica, Hideshima, Teru, Munshi, Nikhil C, Anderson, Kenneth C, Tagliaferri, Pierosandro, Tassone, Pierfrancesco
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Apoptosis Regulatory Proteins - biosynthesis
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Resistance, Neoplasm - genetics
Gene Expression Regulation, Neoplastic - drug effects
Humans
Melphalan - administration & dosage
Mice
MicroRNAs - administration & dosage
MicroRNAs - antagonists & inhibitors
MicroRNAs - biosynthesis
Multidrug Resistance-Associated Proteins - biosynthesis
Multiple Myeloma - drug therapy
Multiple Myeloma - genetics
Multiple Myeloma - pathology
Proto-Oncogene Proteins - biosynthesis
Xenograft Model Antitumor Assays
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Summary:The onset of drug resistance is a major cause of treatment failure in multiple myeloma. Although increasing evidence is defining the role of miRNAs in mediating drug resistance, their potential activity as drug-sensitizing agents has not yet been investigated in multiple myeloma. Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory multiple myeloma cells to melphalan. miR-221/222 expression inversely correlated with melphalan sensitivity of multiple myeloma cells. Inhibition of miR-221/222 overcame melphalan resistance and triggered apoptosis of multiple myeloma cells in vitro, in the presence or absence of human bone marrow (BM) stromal cells. Decreased multiple myeloma cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ABC transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory multiple myeloma xenografts with systemic locked nucleic acid (LNA) inhibitors of miR-221 (LNA-i-miR-221) plus melphalan overcame drug resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice. Taken together, our findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan resistance in preclinical models of multiple myeloma, providing the framework for clinical trials to overcome drug resistance, and improve patient outcome in multiple myeloma.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-15-0489