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

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

Research output: Contribution to journalArticle

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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 p38α 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 TNFα-induced adhesion of MM cells to BMSCs through an ICAM-1- and VCAM-1-independent mechanism. Microarray analysis revealed a novel set of TNFα-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 TNFα-induced MM adhesion. Lastly, we show that SCIO-469 inhibits secretion and expression of the osteoclast-activating factors IL-11, RANKL, and MIP-1α 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.

Original languageEnglish (US)
Pages (from-to)1909-1923
Number of pages15
JournalExperimental Cell Research
Volume312
Issue number10
DOIs
StatePublished - Jun 10 2006
Externally publishedYes

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Osteoclasts
Multiple Myeloma
Cell Adhesion
Bone Marrow
Cell Proliferation
Stromal Cells
p38 Mitogen-Activated Protein Kinases
Chemokine CCL8
Chemokine CXCL10
Interleukin-11
Vascular Cell Adhesion Molecule-1
Intercellular Adhesion Molecule-1
Microarray Analysis
Protein Kinase Inhibitors
Coculture Techniques
Mesenchymal Stromal Cells
Chemokines
Vascular Endothelial Growth Factor A
SCIO-469
Interleukin-6

Keywords

  • Bone marrow microenvironment
  • CCL8
  • Cell adhesion
  • Chemokines
  • CXCL10
  • IL-6
  • Osteoclast formation
  • p38 MAPK inhibitor
  • SCIO-469
  • VEGF

ASJC Scopus subject areas

  • Cell Biology

Cite this

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

In: Experimental Cell Research, Vol. 312, No. 10, 10.06.2006, p. 1909-1923.

Research output: Contribution to journalArticle

Nguyen, AN, Stebbins, EG, Henson, M, O'Young, G, Choi, SJ, Quon, D, Damm, D, Reddy, M, Ma, JY, Haghnazari, E, Kapoun, AM, Medicherla, S, Protter, A, Schreiner, GF, Kurihara, N, Anderson, J, Roodman, GD, Navas, TA & Higgins, LS 2006, 'Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation', Experimental Cell Research, vol. 312, no. 10, pp. 1909-1923. https://doi.org/10.1016/j.yexcr.2006.02.026
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. / Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation. In: Experimental Cell Research. 2006 ; Vol. 312, No. 10. pp. 1909-1923.
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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 p38α 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 TNFα-induced adhesion of MM cells to BMSCs through an ICAM-1- and VCAM-1-independent mechanism. Microarray analysis revealed a novel set of TNFα-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 TNFα-induced MM adhesion. Lastly, we show that SCIO-469 inhibits secretion and expression of the osteoclast-activating factors IL-11, RANKL, and MIP-1α 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.",
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AU - Nguyen, Aaron N.

AU - Stebbins, Elizabeth G.

AU - Henson, Margaret

AU - O'Young, Gilbert

AU - Choi, Sun J.

AU - Quon, Diana

AU - Damm, Debby

AU - Reddy, Mamatha

AU - Ma, Jing Y.

AU - Haghnazari, Edwin

AU - Kapoun, Ann M.

AU - Medicherla, Satyanarayana

AU - Protter, Andy

AU - Schreiner, George F.

AU - Kurihara, Noriyoshi

AU - Anderson, Judy

AU - Roodman, G. David

AU - Navas, Tony A.

AU - Higgins, Linda S.

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N2 - 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 p38α 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 TNFα-induced adhesion of MM cells to BMSCs through an ICAM-1- and VCAM-1-independent mechanism. Microarray analysis revealed a novel set of TNFα-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 TNFα-induced MM adhesion. Lastly, we show that SCIO-469 inhibits secretion and expression of the osteoclast-activating factors IL-11, RANKL, and MIP-1α 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.

AB - 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 p38α 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 TNFα-induced adhesion of MM cells to BMSCs through an ICAM-1- and VCAM-1-independent mechanism. Microarray analysis revealed a novel set of TNFα-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 TNFα-induced MM adhesion. Lastly, we show that SCIO-469 inhibits secretion and expression of the osteoclast-activating factors IL-11, RANKL, and MIP-1α 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.

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KW - VEGF

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