SCIO-469, a Potent and Selective Inhibitor of the p38a MAPK, Inhibits TNFa-Induced Adhesion of Multiple Myeloma Cells to Bone Marrow Stromal Cells Via Downregulation of Chemokines CXCL10/IP-10 and CCL8.

Multiple myeloma (MM) is a plasma cell cancer characterized by the accumulation and clonal expansion of malignant cells in the bone marrow (BM). Recent findings indicate that adhesion of MM cells to BM stromal cells (BMSCs) protects MM cells from drug-induced apoptosis and leads to upregulation of interleukin-6 (IL-6), a cytokine that promotes MM cell growth and survival. However, the molecular mechanism that determines the adhesion of MM cells to BMSCs is relatively unclear. Here we show that SCIO-469, a potent and selective inhibitor of the p38a mitogen-activated protein kinase (MAPK), prevents TNFa-induced adhesion of MM cells to BMSCs. Interestingly, TNFa-induced expression of ICAM-1 and VCAM-1, molecules that have been reported to mediate cell-cell adhesion, is not affected by SCIO-469 treatment. In an effort to identify additional factors that may play a role in the adhesion of MM cells to BMSCs, we performed a DNA microarray experiment on BMSCs. Of the BMSC genes that were strongly upregulated by TNFa exposure and reversed by SCIO-469 treatment, a set of chemokines was most prominent. To determine whether these chemokines are important for MM adhesion to BMSCs, various chemokines (CCL2, CCL7, CCL8, CXCL1, CXCL3, CXCL6, CXCL10/IP-10, and CXCL11) were added together with SCIO-469 in the adhesion assays. We found that reintroduction of the chemokines CXCL10 and CCL8 reversed the inhibition of adhesion by SCIO-469. These results suggest that SCIO-469 inhibits TNFa-induced adhesion of MM cells to BMSCs by downregulating the chemokines CXCL10 and CCL8. Intriguingly, these two chemokines were also recently demonstrated to be involved in leukocyte adhesion to endothelial cells. Thus, chemokines, especially CXCL10 and CCL8, appear to have a general function of localizing blood cells to various sites within the body. Together, our findings demonstrate another potential therapeutic role for SCIO-469 in MM in addition to its role of inhibiting the production of growth factors such as IL-6 and VEGF in the MM bone marrow microenvironment.