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PS-341 (pyrazylcarbonyl-Phe-Leu-boronate, bortezomib, Velcade™) represents a class of peptide boronate proteasome inhibitors which inhibit 26S proteasome activity, and demonstrated promise as potential novel anti-cancer therapies. PS-341: induces heat shock proteins (Hsps); activates JNK; induces apoptosis in MM cells mediated by activation of caspase-8, -9, and -3; induces cleavage of DNA protein kinase catalytic subunit (DNA-PKcs) and ATM; overcomes conventional drug resistance conferred by IL-6 or adherence to bone marrow stromal cells (BMSCs); and further abrogates IL-6-triggered signaling cascades by caspase-dependent downregulation of gp130 (CD130). Importantly, a phase II clinical trial of Velcade in refractory relapsed MM demonstrated 35% responses, including 10% complete and near complete responses; however, 65% of patients did not respond to PS-341. 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) alone did not induce significant growth inhibition in MM.1S cells, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK, as well as upregulation of Hsp27, associated with enhanced cytotoxicity. Importantly, SCIO-469 enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly (ADP)-ribose polymerase (PARP). Moreover, SCIO-469 downregulated PS-341-induced increases in G2/M phase cells, associated with downregulation of p21Cip1 expression. These results were further confirmed using transient transfection with p38 MAPK siRNA. 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.