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Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation
Authors:Nguyen Aaron N  Stebbins Elizabeth G  Henson Margaret  O'Young Gilbert  Choi Sun J  Quon Diana  Damm Debby  Reddy Mamatha  Ma Jing Y  Haghnazari Edwin  Kapoun Ann M  Medicherla Satyanarayana  Protter Andy  Schreiner George F  Kurihara Noriyoshi  Anderson Judy  Roodman G David  Navas Tony A  Higgins Linda S
Institution:Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
Abstract:The multiple myeloma (MM) bone marrow (BM) microenvironment plays a critical role in supporting tumor growth and survival as well as in promoting formation of osteolytic lesions. Recent results suggest that the p38 mitogen-activated protein kinase (MAPK) is an important factor in maintaining this activated environment. In this report, we demonstrate that the p38alpha MAPK inhibitor, SCIO-469, suppresses secretion of the tumor-supportive factors IL-6 and VEGF from BM stromal cells (BMSCs) as well as cocultures of BMSCs with MM cells, resulting in reduction in MM cell proliferation. Additionally, we show that SCIO-469 prevents TNFalpha-induced adhesion of MM cells to BMSCs through an ICAM-1- and VCAM-1-independent mechanism. Microarray analysis revealed a novel set of TNFalpha-induced chemokines in BMSCs that is strongly inhibited by SCIO-469. Furthermore, reintroduction of chemokines CXCL10 and CCL8 to BMSCs overcomes the inhibitory effect of SCIO-469 on TNFalpha-induced MM adhesion. Lastly, we show that SCIO-469 inhibits secretion and expression of the osteoclast-activating factors IL-11, RANKL, and MIP-1alpha as well as prevents human osteoclast formation in vitro. Collectively, these results suggest that SCIO-469 treatment can suppress factors in the bone marrow microenvironment to inhibit MM cell proliferation and adhesion and also to alleviate osteolytic activation in MM.
Keywords:p38 MAPK inhibitor  SCIO-469  Bone marrow microenvironment  IL-6  VEGF  Cell adhesion  Chemokines  CXCL10  CCL8  Osteoclast formation
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