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

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posted on 2023-03-31, 18:24 authored by Annamaria Gullà, Maria Teresa Di Martino, Maria Eugenia Gallo Cantafio, Eugenio Morelli, Nicola Amodio, Cirino Botta, Maria Rita Pitari, Santo Giovanni Lio, Domenico Britti, Maria Angelica Stamato, Teru Hideshima, Nikhil C. Munshi, Kenneth C. Anderson, Pierosandro Tagliaferri, Pierfrancesco Tassone

Supplementary methods for pubblication only

Funding

Italian Association for Cancer Research (AIRC), PI: Pierfrancesco Tassone, “Special Program Molecular Clinical Oncology- 5 per mille”

NIH

“Fondazione Umberto Veronesi” Fellowship

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ARTICLE ABSTRACT

Purpose: 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.Experimental Design: Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory multiple myeloma cells to melphalan.Results: 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.Conclusions: 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. Clin Cancer Res; 22(5); 1222–33. ©2015 AACR.

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    Clinical Cancer Research

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    Drug MechanismsDrug-mediated stimulation of cell death pathwaysDrug ResistanceDrug transport and metabolismNovel mechanismsRegulation of gene expression in drug resistanceReversal of drug resistanceTransporter-based drug resistanceGene RegulationPosttranscriptional and translational controlOncogenes & Tumor SuppressorsSmall Molecule AgentsAlkylating agents

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