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

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.

• Authors: Aaron N Nguyen, Elizabeth G Stebbins, Margaret Henson, Gilbert O'Young, Sun J Choi, Diana Quon, Debby Damm, Mamatha Reddy, Jing Y Ma, Edwin Haghnazari, Ann M Kapoun, Satyanarayana Medicherla, Andy Protter, George F Schreiner, Noriyoshi Kurihara, Judy Anderson, G David Roodman, Tony A Navas, Linda S Higgins
• Journal: Experimental cell research (Exp Cell Res) Vol. 312 Issue 10 Pg. 1909-23 (Jun 10 2006) ISSN: 0014-4827 [Print] United States
• PMID: 16600214 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Animals
• Bone Marrow (chemistry, 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, pathology)
• Oligonucleotide Array Sequence Analysis
• Osteoclasts (cytology, physiology)
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Stromal Cells (cytology, metabolism)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)