HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide
| Autor: | Luciano Cascione, Jessica Consiglio, Nicola Zanesi, Yvonne A. Efebera, Lara Rizzotto, Andrew Stiff, Flavia Pichiorri, Alessandro Canella, Balveen Kaur, Enrico Caserta, John C. Byrd, Hector Cordero Nieves, Hanna S. Radomska, Xiaokui Mo, Volinia Stefano, Emily Smith, Craig C. Hofmeister, Douglas W. Sborov |
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| Rok vydání: | 2015 |
| Předmět: |
Gerontology
Blotting Western lenalidomide Mice Nude Angiogenesis Inhibitors Apoptosis Enzyme-Linked Immunosorbent Assay Real-Time Polymerase Chain Reaction Phenylbutyrate Immunoenzyme Techniques Mice In vivo medicine Tumor Cells Cultured Animals Humans RNA Messenger CD44 Dexamethasone Multiple myeloma Lenalidomide Cell Proliferation IGF2BP3 business.industry Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling medicine.disease Flow Cytometry miR-9–5p Phenylbutyrates Xenograft Model Antitumor Assays 3. Good health Thalidomide Histone Deacetylase Inhibitors medicine.anatomical_structure Hyaluronan Receptors myeloma Oncology Drug Resistance Neoplasm Cancer research Drug Therapy Combination Female Bone marrow HDAC Inhibitor AR-42 business Multiple Myeloma medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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