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p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells

Oncogene volume 23, pages 8766–8776 (2004)Cite this article

Abstract

Although PS-341 (bortezomib) is a promising agent to improve multiple myeloma (MM) patient outcome, 65% of patients with relapsed and refractory disease do not respond. We have previously shown that heat shock protein (Hsp)27 is upregulated after PS-341 treatment, that overexpression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcomes PS-341 resistance. Since Hsp27 is a downstream target of p38 mitogen-activated protein kinase (MAPK)/MAPK-mitogen-activated protein kinase-2 (MAPKAPK2), we hypothesized that inhibition of p38 MAPK activity could augment PS-341 cytotoxicity by downregulating Hsp27. Although p38 MAPK inhibitor SCIO-469 (Scios Inc, CA, USA) alone did not induce significant growth inhibition, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK as well as upregulation of Hsp27, associated with enhanced cytotoxicity in MM.1S cells. Importantly, SCIO-469 enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly(ADP)-ribose polymerase. Moreover, SCIO-469 downregulated PS-341-induced increases in G2/M-phase cells, associated with downregulation of p21Cip1 expression. Importantly, SCIO-469 treatment augmented cytotoxicity of PS-341 even against PS-341-resistant cell lines and patient MM cells. These studies therefore provide the framework for clinical trials of SCIO-469 to enhance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM.

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Acknowledgements

We thank Sarvajit Chakravarty, Sundeep Dugar, Gregory Leudtke, Babu Mavunkel, John Perumattam, Greg Luedtke, Sundeep Dugar, and Sarvajit Chakravarty for SCIO-469. This study is supported by Scios Fellowship in Multiple Myeloma Research (TH), National Institutes of Health Grants Specialized Programs of Research Excellence (SPORE) IP50 CA10070-01, PO-1 78378 and RO-1 CA 50947; the Doris Duke Distinguished Clinical Research Scientist Award (KCA); the Multiple Myeloma Research Foundation (TH); and the Cure for Myeloma Research Fund (KCA).

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Mayer 557, 44 Binney Street, Boston, 02115, MA, USA

    Teru Hideshima, Klaus Podar, Dharminder Chauhan, Kenji Ishitsuka, Constantine Mitsiades, Yu-Tzu Tai, Makoto Hamasaki, Noopur Raje, Hiromasa Hideshima, Nikhil C Munshi, Paul G Richardson & Kenneth C Anderson

  2. Scios Inc., 6500 Paseo Padre Parkway, Fremont, 94555, CA, USA

    George Schreiner, Aaron N Nguyen, Tony Navas & Linda S Higgins

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  1. Teru Hideshima
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Correspondence to Kenneth C Anderson.

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Hideshima, T., Podar, K., Chauhan, D. et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 23, 8766–8776 (2004). https://doi.org/10.1038/sj.onc.1208118

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