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Romidepsin Overcomes Cell Adhesion-Mediated Drug Resistance in Multiple Myeloma Cells

5] . These effects might ultimately affect the expression and function of various intracellular molecules, including transcription factors. We therefore hypothesized that these agents influence the expression levels of adhesion molecules in MM cells. To verify this hypothesis, we examined the effect of the HDI romidepsin and DNAmethylating agent azacitidine on the expression levels of CD49d and two other representative adhesion molecules, CD29 and CD138, by flow cytometry analyses in two human MM cell lines, RPMI8226 and U266. Surprisingly and importantly, romidepsin repressed the expression levels of CD49d with statistical significance in both cell lines ( fig. 1 a, b). Levels of CD49d mRNA also markedly decreased after addition of romidepsin, suggesting that romidepsin suppresses CD49d expression at the mRNA level ( fig. 1 c). In contrast, romidepsin had no significant effect on the expression levels of CD29 and CD138 ( fig. 1 a, b). In RPMI8226 cells, azacitidine also repressed CD49d as well as CD138 ( fig. 1 a). However, in U266 cells it had no influence on all three adhesion molecules tested, including CD49d ( fig. 1 b). Since azacitidine failed to disrupt DNA methyltransferases, which are its main targets, in U266 cells [unpubl. data], it is possible that azacitidine had no effect on the pathophysiology of these cells. Multiple myeloma (MM) is a malignant hematopoietic disease that remains incurable. Therapeutic strategies for this disease have been rapidly progressing based on the development of new drugs, including proteasome inhibitors, immunomodulatory agents, antibodies and small molecular compounds such as histone deacetylase inhibitors (HDIs); however, drug resistance remains a major challenge [1] . It is well known that cell adhesionmediated drug resistance (CAM-DR) occurs when MM cells interact with stromal cells [2] . Specifically, MM cells express surface adhesion receptor molecules which bind with corresponding ligands on stromal cells. Such interaction results in protection of MM cells from the cytotoxic effects of anti-myeloma drugs. We previously found that MM cells express various adhesion molecules, including CD29 (β1-integrin), CD49d (α4-integrin, a subunit of VLA-4), CD54 (intercellular adhesion molecule-1), CD138 (syndecan-1), CD184 (CXC chemokine receptor-4), and CD44. Furthermore, among them CD49d was crucial for CAM-DR to conventional antimyeloma drugs such as bortezomib and dexamethasone [3] . Thus, it is of great importance to suppress CD49d expression to overcome CAM-DR. HDIand DNA-methylating agents show anti-tumor activity by epigenetically re-expressing various genes [4, Received: August 8, 2013 Accepted after revision: November 10, 2013 Published online: December 12, 2013