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- Title
p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells.
- Authors
Hideshima, Teru; Podar, Klaus; Chauhan, Dharminder; Ishitsuka, Kenji; Mitsiades, Constantine; Tai, Yu-Tzu; Hamasaki, Makoto; Raje, Noopur; Hideshima, Hiromasa; Schreiner, George; Nguyen, Aaron N; Navas, Tony; Munshi, Nikhil C; Richardson, Paul G; Higgins, Linda S; Anderson, Kenneth C
- 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.Oncogene (2004) 23, 8766-8776. doi:10.1038/sj.onc.1208118 Published online 11 October 2004
- Subjects
HYBRIDOMAS; PLASMACYTOMA; PATIENTS; MONOCLONAL gammopathies; PROTEIN kinases; CELLS
- Publication
Oncogene, 2004, Vol 23, Issue 54, p8766
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1208118