title: Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition.
abstract: 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.
authors.affiliation: Department of Pathology, The Methodist Hospital and Research Institute, Houston, TX 77030, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wen
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Feng
authors.forename: Wanting
authors.initials: W
authors.lastname: Huang
authors.forename: Haiyun
authors.initials: H
authors.lastname: Chen
authors.forename: Bing
authors.initials: B
authors.lastname: Liao
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rice
authors.forename: Hector A
authors.initials: HA
authors.lastname: Preti
authors.forename: Rammurti T
authors.initials: RT
authors.lastname: Kamble
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Ballon
authors.forename: Chung-Che
authors.initials: CC
authors.lastname: Chang
mesh_terms: 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
chemical_list: 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