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 |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|