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Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and
Aaron N Nguyen1, Elizabeth G Stebbins, Margaret Henson
1Scios 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.
Insights
The p38alpha MAPK inhibitor SCIO-469 targets the multiple myeloma bone marrow microenvironment. It suppresses tumor growth, adhesion, and osteolytic activation, offering a potential therapeutic strategy for multiple myeloma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The multiple myeloma (MM) bone marrow (BM) microenvironment supports tumor growth and osteolytic lesions.
- p38 mitogen-activated protein kinase (MAPK) signaling is implicated in maintaining this pro-tumorigenic environment.
Purpose of the Study:
- To investigate the therapeutic potential of the p38alpha MAPK inhibitor SCIO-469 in the context of multiple myeloma.
- To elucidate the mechanisms by which SCIO-469 affects the MM bone marrow microenvironment.
Main Methods:
- Treatment of bone marrow stromal cells (BMSCs) and MM cells with SCIO-469.
- Analysis of cytokine and chemokine secretion (IL-6, VEGF, CXCL10, CCL8, IL-11, RANKL, MIP-1alpha).
- Assessment of MM cell proliferation, adhesion to BMSCs, and osteoclast formation in vitro.
Main Results:
- SCIO-469 suppressed IL-6 and VEGF secretion from BMSCs, reducing MM cell proliferation.
- SCIO-469 inhibited TNFalpha-induced MM cell adhesion to BMSCs via a novel mechanism.
- SCIO-469 reduced secretion of osteoclast-activating factors (IL-11, RANKL, MIP-1alpha) and inhibited osteoclast formation.
Conclusions:
- SCIO-469 effectively targets key factors within the MM bone marrow microenvironment.
- SCIO-469 demonstrates potential to inhibit MM cell proliferation, adhesion, and osteolytic bone disease.
