Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition.
The combination of ATO and bortezomib (ATO+bortezomib) has been recently shown to enhance antimyeloma activity; nevertheless, the mechanisms remained unclear in these studies. However, both bortezomib and ATO have been shown to activate the p38 MAPK pathway, which may counteract the enhancement induced by this combination. We studied the cytotoxicity of bortezomib, ATO, and ATO+bortezomib with or without inhibiting p38 MAPK, along with associated molecular changes in myeloma cells. The treatment of myeloma cells with ATO+bortezomib induced higher cytotoxicity than either agent alone. This increased cytotoxicity was further synergistically enhanced by inhibiting p38 MAPK. This effect was preserved in the presence of marrow stromal cells designed to simulate the tumor micro-environment and in the CD138+ neoplastic plasma cells directly isolated from myeloma patients. The enhanced cytotoxicity of ATO+bortezomib was associated with augmented STAT3 inhibition and JNK activation, up-regulation of Bim, p21, p27, p53 as well as down-regulation of Bcl-2. Furthermore, the synergistically potentiated apoptosis by p38 MAPK inhibition was associated with the attenuation of ATO+bortezomib-mediated activation of Hsp27 as well as the enhancement of ATO+bortezomib-mediated JNK activation, p53 up-regulation, and Bcl-2 down-regulation. The results suggest the opportunity for using p38 MAPK inhibition to enhance the efficacy of ATO+bortezomib in myeloma.
Wen
Jianguo
J
Department of Pathology, The Methodist Hospital and Research Institute, Houston, TX 77030, USA.
Feng
Yongdong
Y
Huang
Wanting
W
Chen
Haiyun
H
Liao
Bing
B
Rice
Lawrence
L
Preti
Hector A
HA
Kamble
Rammurti T
RT
Zu
Youli
Y
Ballon
Douglas J
DJ
Chang
Chung-Che
CC
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D000069286:Bortezomib; D004357:Drug Synergism; D004789:Enzyme Activation; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy*; D010087:Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001152:Arsenicals; D001897:Boronic Acids; D055551:HSP27 Heat-Shock Proteins; D010087:Oxides; D011719:Pyrazines; D050796:STAT3 Transcription Factor; D000069286:Bortezomib; D048051:p38 Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide