title: Inhibition of extracellular signal-regulated kinase activity by sorafenib increases sensitivity to DNR in K562 cells.
abstract: The mitogen-activated protein kinase (MAPK) pathway has a protective function on the management of hematologic malignancies. The aim of this study was to assess whether the induction of MAPK-mediated effects contributes to the therapeutic value of combination sorafenib and daunorubicin (DNR) treatment. Herein, we found that DNR increased phosphorylation of extracellular signal-regulated kinases (ERK1/2) in K562 cells. ERK1/2 activity was blocked by either the mitogen-induced extracellular kinase (MEK) inhibitor U0126 or a multi-kinase inhibitor sorafenib. Of note, sorafenib sensitized K562 to DNR by inhibiting proliferation and inducing apoptosis in a dose-dependent manner which was through blocking the RAF/MEK/ERK pathway. Moreover, K562 cells transfected with a constitutively active MEK2DD plasmid showed increasing IC50 values following DNR treatment compared with control cells. Combination of DNR with MEK inhibitor U0126 synergistically inhibited K562 cell growth. In conclusion, our results indicated that sorafenib sensitized K562 cells to DNR-induced cytotoxicity by downregulating p-ERK1/2 expression. DNR in combination with sorafenib may represent a new and potential therapeutic strategy in treating acute leukemia with high p-ERK1/2 levels.
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China. xiaorzh@126.com
authors.forename: Ruo-Zhi
authors.initials: RZ
authors.lastname: Xiao
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: He
authors.forename: Mu-Jun
authors.initials: MJ
authors.lastname: Xiong
authors.forename: Xing-Xing
authors.initials: XX
authors.lastname: Ruan
authors.forename: Li-Lin
authors.initials: LL
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002070:Butadienes; D009570:Nitriles; D010671:Phenylurea Compounds; C113580:U 0126; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D003630:Daunorubicin