In Vitro and in Vivo Anti-tumor Activity of miR-221/222 Inhibitors in Multiple Myeloma

Abstract

// Maria Teresa Di Martino 1,2 , Annamaria Gullà 1 , Maria Eugenia Gallo Cantafio 1 , Marta Lionetti 3 , Emanuela Leone 1 , Nicola Amodio 1 , Pietro Hiram Guzzi 4 , Umberto Foresta 1 , Francesco Conforti 2 , Mario Cannataro 4 , Antonino Neri 3 , Antonio Giordano 5,6 , Pierosandro Tagliaferri 1,2 , and Pierfrancesco Tassone 1,2,6 1 Department of Experimental and Clinical Medicine, Magna Graecia University,  Catanzaro, Italy  2 Medical Oncology, Tommaso Campanella Cancer Center, Catanzaro, Italy 3 Department of Medical Sciences University of Milan, Hematology1, IRCCS Policlinico Foundation, Milan, Italy; 4 Department of Medical and Surgical Sciences, Laboratory of Bioinformatics Unit; 5 Department of Human Pathology and Oncology, University of Siena, Siena, Italy; 6 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA Correspondence: Pierfrancesco Tassone, email: // Keywords : miR-221, miR-222, microRNA, miRNA, multiple myeloma, plasma cell leukemia Received : January 15, 2013 Accepted : February 22, 2013 Published : February 24, 2013 Abstract A rising body of evidence suggests that silencing microRNAs (miRNAs) with oncogenic potential may represent a successful therapeutic strategy for human cancer. We investigated the therapeutic activity of miR-221/222 inhibitors against human multiple myeloma (MM) cells. Enforced expression of miR-221/222 inhibitors triggered in vitro anti-proliferative effects and up-regulation of canonic miR-221/222 targets, including p27Kip1, PUMA, PTEN and p57Kip2, in MM cells highly expressing miR-221/222. Conversely, transfection of miR-221/222 mimics increased S-phase and down-regulated p27Kip1 protein expression in MM with low basal miR-221/222 levels. The effects of miR-221/222 inhibitors was also evaluated in MM xenografts in SCID/NOD mice. Significant anti-tumor activity was achieved in xenografted mice by the treatment with miR-221/222 inhibitors, together with up-regulation of canonic protein targets in tumors retrieved from animals. These findings provide proof of principle that silencing the miR-221/222 cluster exerts significant therapeutic activity in MM cells with high miR-221/222 level of expression, which mostly occurs in TC2 and TC4 MM groups. These findings suggest that MM genotyping may predict the therapeutic response. All together our results support a framework for clinical development of miR-221/222 inhibitors-based therapeutic strategy in this still incurable disease.