P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells.
The resistance to arsenic trioxide (ATO) treatment is relatively common (55-80%) in multiple myeloma patients. This study found that ATO at clinically achievable concentrations (2-7 mumol/l) activated p38 mitogen-activated protein kinase (MAPK) in both myeloma cell lines and primary myeloma cells, a finding not previously well-documented in myeloma cells. Inhibition of p38 MAPK activation by pharmacological inhibitors (SB203580) or downregulation of p38 MAPK by siRNA significantly increased the apoptosis and/or growth inhibition induced by ATO treatment in myeloma cells. Combination of ATO and p38 MAPK inhibition abolished the interleukin-6 enhanced protection of myeloma cells against ATO treatment. The ATO-resistant cell line developed in our laboratory showed an increase in p38 MAPK activation. The increase of apoptosis by the combination of ATO and SB203580 was accompanied by the activation of caspase-9 and caspase-8 suggesting that both extrinsic and intrinsic apoptotic pathways are involved. Additionally, the p38 MAPK activation by ATO was associated with increased phosphorylation and upregulated expression of Heat shock protein 27. These results suggest that ATO-induced p38 MAPK activation plays an important role in the resistance to ATO in myeloma cells and that p38 MAPK inhibition may overcome resistance to ATO treatment in myeloma patients.
Wen
Jianguo
J
Department of Pathology, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, TX, USA.
Cheng
Haiyun Y
HY
Feng
Yongdong
Y
Rice
Lawrence
L
Liu
Shangfeng
S
Mo
Albert
A
Huang
James
J
Zu
Youli
Y
Ballon
Douglas J
DJ
Chang
Chung-Che
CC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018832:Molecular Chaperones; D009101:Multiple Myeloma / Q000201:enzymology / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007093:Imidazoles; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D010087:Oxides; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C093642:SB 203580; D000077237:Arsenic Trioxide