OSU-03012 sensitizes TIB-196 myeloma cells to imatinib mesylate via AMP-activated protein kinase and STAT3 pathways.
Although c-Kit is expressed on the surface of myeloma cells in one-third of myeloma patients, the efficacy of imatinib mesylate for patients with myeloma is still controversial. To investigate the combinatorial effect of OSU-03012 and imatinib mesylate, we treated a c-Kit-expressing myeloma cell line, TIB-196, with DMSO, OSU-03012 alone, imatinib mesylate alone and OSU-03012 plus imatinib mesylate. OSU-03012 sensitized TIB-196 cells to imatinib mesylate cytotoxicity. p-STAT3 (Tyr705), as well as down-stream cyclin D1 and Mcl-1, was down regulated. Additionally, there was markedly increased p-AMPK (Thr172) and down-regulation of p-p70S6K (Thr386) in the combination group. Combined treatments targeting c-Kit, AMPK and STAT3 may be a potential strategy for treating patients with myeloma.
Bai
Li-Yuan
LY
Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
Weng
Jing-Ru
JR
Tsai
Chen-Hsun
CH
Sargeant
Aaron
A
Lin
Cheng-Wen
CW
Chiu
Chang-Fang
CF
D055372:AMP-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D001549:Benzamides; C500894:OSU 03012; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D000068877:Imatinib Mesylate; D055372:AMP-Activated Protein Kinases