title: A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gullà
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Gallo Cantafio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Morelli
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Pitari
authors.affiliation: Pathology Unit, "Giovanni Paolo II" Hospital, Lamezia Terme, Catanzaro, Italy.
authors.forename: Santo Giovanni
authors.initials: SG
authors.lastname: Lio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Britti
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Maria Angelica
authors.initials: MA
authors.lastname: Stamato
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts. VA Boston Healthcare System, West Roxbury, Boston, Massachusetts.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy. Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, Pennsylvania. tassone@unicz.it.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008558:Melphalan / Q000008:administration & dosage*; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D008558:Melphalan; D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011518:Proto-Oncogene Proteins; C438378:BBC3 protein, human; C000592539:LNA-i-miR-221; C525709:MIR221, human; C525710:MIR222, human; C421109:multidrug resistance-associated protein 1