Blockade of SDF-1/CXCR4 reduces adhesion-mediated chemoresistance of multiple myeloma cells via interacting with interleukin-6.

Resistance to chemotherapy represents a major cause for treatment failure in multiple myeloma (MM). Herein, this study was conducted to explore the effect of SDF-1/CXCR4 and interleukin-6 (IL-6) in MM cell adhesion-mediated chemoresistance. Enzyme-linked immunosorbent assay was applied to detect expressions of SDF-1α and IL-6 in MM patients and healthy controls. RPMI-8226 cells and isolated bone marrow stromal cells (BMSCs) were stimulated using recombinant SDF-1α and IL-6. Effect of cocultured BMSCs and RPMI-8226 cells on chemosensitivity and apoptosis of RPMI-8226 cells was analyzed. Effect of doxorubicin on the adhesion rate of RPMl-8226 cells to BMSCs was analyzed by calcitonin test. Effect of SDF-1α-induced upregulation of IL-6 on chemotherapeutic resistance and apoptosis of RPMI-8226 cells in adhesion state was analyzed. Cell adhesion model was treated with recombinant protein SDF-1α and phosphoinositide 3-kinase (P13K) inhibitor Wortmarmin. The levels of P13K and protein kinase B (AKT) and its phosphorylation as well as the expression of IL-6 were analyzed. SDF-1α was positively correlated with IL-6. Recombinant human SDF-1α increased IL-6 expression and induced IL-6 secretion in a time- and dose-dependent manner in BMSCs, which was inhibited by IL-6 and SDF-1α neutralizing antibodies. Coculture of MM cells with BMSCs increased the drug resistance and inhibited the apoptosis on MM cells. SDF-1α-induced IL-6 upregulation mediates chemoresistance and apoptosis of RPMI-8226 cells in adhesion state. SDF-1α may up-regulate the expression of IL-6 by activating the P13K/AKT signaling pathway. SDF-1/CXCR4 may up-regulate the expression of IL-6 through the activation of the P13K/AKT signaling pathway, thereby affecting the chemoresistance mediated by adhesion in MM cells.