Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

“…These correlations could support the contention that high PPP3CA expression levels might be involved in the pathogenesis of MM. An important role in cell adhesion-mediated drug resistance (CAM-DR) to bortezomib and conventional chemotherapy in MM is played by α 4 integrins (23). Expression of α 4 integrins tended to be high in MM patients with elevated PPP3CA expression, and the possible relevance of high PPP3CA expression to drug resistance was also supposed ( Figure 1D).…”

The mesenchymal tumor microenvironment

“…Therefore, knockdown expression of a 4 -integrins in multiple myeloma cells constitutes an effective way to sensitize these cells to bortezomib, a proteome inhibitor drug often used in multiple myeloma patients. 127 To this end, natalizumab, a novel small adhesion molecule inhibitor that interferes with a 4 β 1 -and a 4 β 7 -integrins, is believed to prevent multiple myeloma cell interactions with both stromal cells and stromal ECM as well as indirectly interfere with VEGF secretion and insulin-like growth factor induced signaling in the bone marrow where it increases sensitivity to bortezomib and dexamethasone. 128 These observations point to the potential clinical use of natalizumab for patients with relapsing multiple myeloma and other malignancies.…”

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

“…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 anti-myeloma drugs such as bortezomib and dexamethasone [3]. Thus, it is of great importance to suppress CD49d expression to overcome CAM-DR. …”

“…To clarify whether romidepsin-mediated suppression of CD49d expression results in abrogation of CAM-DR to other drugs, we assessed CAM-DR to bortezomib, melphalan and dexamethasone, which are key drugs for MM therapy, using the co-culture system as described previously [3]. In the absence of the stromal cell line UBE6T-7, bortezomib, melphalan and dexamethasone significantly increased the percentage of annexin-V-positive cells, suggesting that these agents effectively induce apoptosis.…”