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

Abstract

Purpose The onset of drug-resistance is a major cause of treatment failure in multiple myeloma (MM). While increasing evidence is defining the role of microRNAs in mediating drug-resistance, their potential activity as drug-sensitizing agents has not yet been investigated in MM. Experimental Design Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory MM cells to melphalan. Results MiR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM 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 ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic 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 MM, providing the framework for clinical trials to overcome drug resistance and improve patient outcome in MM.

A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival

“…To this aim, current research will gain the best advantage from the new emerging scenario of functional network of non-coding RNAs, such as miRNAs and long non-coding RNAs, that already demonstrated their role in the control of different (immune-) cell functions and in cancer biology, and are approaching the clinical side. 58, 59, 60, 61 In conclusion, we provide proof-of-concept that MM cells drive a pro-inflammatory effect in the BMM, which is relevant in the disease evolution. The inflammatory signatures here reported, which differentiate disease phases and offer a novel prognostic tool, might be relevant for the design of novel individualized treatment of MM.…”

MicroRNA‐26a inhibits multiple myeloma cell growth by suppressing cyclin‐dependent kinase 6 expression

“…MiRNAs are involved in the physiological and pathological processes of MM, and can be as a potential target for drug discovery in MM . Recent studies reported that inhibition of miR‐221 restored drug sensitivity in melphalan‐refractory MM cells, and targeting the miR‐221‐222/PUMA/BAK/BAX pathway abrogated dexamethasone resistance in MM . Synthetic miRNA‐125b‐5p mimics selectively targeted IRF4 and inhibited MM cell growth both in vitro and in vivo .…”

MicroRNAs and exosomes: Small molecules with big actions in multiple myeloma pathogenesis

“…Furthermore, LNA‐i‐miR‐221 was shown to perform anti‐MM property via systemic delivery. They also revealed the rationale of the combined application of melphalan and LNA‐i‐miR‐221 in drug‐refractory stage of MM patients …”