Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation

Exp Cell Res. 2006 Jun 10;312(10):1909-23. doi: 10.1016/j.yexcr.2006.02.026. Epub 2006 Apr 4.


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.

MeSH terms

  • Animals
  • Bone Marrow* / chemistry
  • Bone Marrow* / metabolism
  • Carrier Proteins / metabolism
  • Cell Adhesion / physiology*
  • Cell Proliferation*
  • Chemokines / metabolism
  • Coculture Techniques
  • Culture Media, Conditioned
  • Humans
  • Indoles / metabolism*
  • Interleukin-6 / metabolism
  • Membrane Glycoproteins / metabolism
  • Multiple Myeloma* / metabolism
  • Multiple Myeloma* / pathology
  • Oligonucleotide Array Sequence Analysis
  • Osteoclasts / cytology
  • Osteoclasts / physiology*
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Stromal Cells / cytology
  • Stromal Cells / metabolism
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Carrier Proteins
  • Chemokines
  • Culture Media, Conditioned
  • Indoles
  • Interleukin-6
  • Membrane Glycoproteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • SCIO-469
  • TNFRSF11A protein, human
  • TNFSF11 protein, human
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • p38 Mitogen-Activated Protein Kinases