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Myelodyspasias

Inhibition of p38α MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-XL, Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo

Leukemia volume 20, pages 1017–1027 (2006)Cite this article

Abstract

Inhibition of p38 kinase blocks the production of tumor-promoting factors in the multiple myeloma (MM) bone marrow microenvironment. Proteasome inhibitors MG132 and bortezomib have been shown to have direct cytotoxic effects on MM cells. We show that a selective inhibitor of p38α, SCIO-469, enhances the ability of MG132 and bortezomib to induce the apoptosis of MM cells. Previously, we showed that p38 inhibition with SCIO-469 enhances MM cytotoxicity of bortezomib by inhibiting the transient expression and phosphorylation of Hsp27, a downstream target of p38. Here we show that continued treatment of MM cells with bortezomib leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis. Furthermore, we show that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and downregulation of Bcl-XL and Mcl-1. In a mouse xenograft plasmacytoma model of MM, we found that inhibiting p38 augments the effects of bortezomib in decreasing MM tumor growth in vivo. Thus, in addition to its role in suppressing an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic factors in MM cells, suggesting great potential for co-therapy.

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Acknowledgements

We thank Richard Brewer, former President of Scios Inc., for his heartfelt support and inspiration for this project. All of the authors, except TH and KCA, are employed by Scios Inc., where SCIO-469, a potential product, was studied in the present work. This paper has not been submitted elsewhere while under consideration for Leukemia.

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Authors and Affiliations

  1. Scios, Inc., Fremont, CA, USA

    T A Navas, A N Nguyen, M Reddy, J Y Ma, E Haghnazari, M Henson, E G Stebbins, I Kerr, G O'Young, A M Kapoun, S Chakravarty, B Mavunkel, J Perumattam, G Luedtke, S Dugar, S Medicherla, A A Protter, G F Schreiner & L S Higgins

  2. Dana-Farber Cancer Institute, Boston, MA, USA

    T Hideshima & K C Anderson

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  1. T A Navas
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Correspondence to L S Higgins.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Navas, T., Nguyen, A., Hideshima, T. et al. Inhibition of p38α MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-XL, Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia 20, 1017–1027 (2006). https://doi.org/10.1038/sj.leu.2404200

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