p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells.
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.
Hideshima
Teru
T
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Mayer 557, 44 Binney Street, Boston, MA 02115, USA.
Podar
Klaus
K
Chauhan
Dharminder
D
Ishitsuka
Kenji
K
Mitsiades
Constantine
C
Tai
Yu-Tzu
YT
Hamasaki
Makoto
M
Raje
Noopur
N
Hideshima
Hiromasa
H
Schreiner
George
G
Nguyen
Aaron N
AN
Navas
Tony
T
Munshi
Nikhil C
NC
Richardson
Paul G
PG
Higgins
Linda S
LS
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D006360:Heat-Shock Proteins; D011719:Pyrazines; D000069286:Bortezomib; D048051:p38 Mitogen-Activated Protein Kinases