HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide
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Alessandro Canella1,*, Hector Cordero Nieves1,*, Douglas W. Sborov2, Luciano Cascione3, Hanna S. Radomska1, Emily Smith4, Andrew Stiff1, Jessica Consiglio1,9, Enrico Caserta1, Lara Rizzotto1, Nicola Zanesi1, Volinia Stefano5, Balveen Kaur6, Xiaokui Mo7, John C. Byrd1,8, Yvonne A. Efebera8, Craig C. Hofmeister8, Flavia Pichiorri1,8
1Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
2Department of Internal Medicine, Oncology/Hematology Fellowship, The Ohio State University, Columbus, OH, USA
3Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland
4Department of Internal Medicine, Biomedical Sciences Graduate Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
5Department of Internal Medicine, Biosystems Analysis, LTTA, Department of Morphology, Surgery and Experimental Medicine, Università degli Studi, Ferrara, Italy
6Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Medical Center, Columbus, Ohio, USA
7Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH, USA
8Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA
9Present Address: Sanford Burnham Prebys Medical Discovery Insitute, La Jolla, CA, USA
*These authors have contributed equally to this work
Flavia Pichiorri, e-mail: Flavia.Pichiorri@osumc.edu
Craig C. Hofmeister, e-mail: Craig.Hofmeister@osumc.edu
Keywords: myeloma, CD44, miR-9–5p, IGF2BP3, lenalidomide
Received: July 22, 2015 Accepted: September 14, 2015 Published: September 25, 2015
Multiple myeloma (MM) is a hematological malignancy of plasma cells in the bone marrow. Despite multiple treatment options, MM is inevitably associated with drug resistance and poor outcomes. Histone deacetylase inhibitors (HDACi's) are promising novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with MM. Although in preclinical studies HDACi's have proven anti-myeloma activity, but in the clinic single-agent HDACi treatments have been limited due to low tolerability. Improved clinical outcomes were reported only when HDACi's were combined with other drugs. Here, we show that a novel pan-HDACi AR-42 downregulates CD44, a glycoprotein that has been associated with lenalidomide and dexamethasone resistance in myeloma both in vitro and in vivo. We also show that this CD44 downregulation is in part mediated by miR-9–5p, targeting insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly binds to CD44 mRNA and increases its stability. Importantly, we also demonstrate that AR-42 enhances anti-myeloma activity of lenalidomide in primary MM cells isolated from lenalidomide resistant patients and in in vivo MM mouse model. Thus, our findings shed light on potential novel combinatorial therapeutic approaches modulating CD44 expression, which may help overcome lenalidomide resistance in myeloma patients.
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