title: Imatinib has the potential to exert its antileukemia effects by down-regulating hERG1 K+ channels in chronic myelogenous leukemia.
abstract: Imatinib is a powerful protein tyrosine kinase (PTK) inhibitor that specifically targets BCR-ABL, KIT, and PDGFR kinases, has become the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Beside PTKs, PTK inhibitors alter the activity of a large number of voltage-dependent ion channels. hERG1 K(+) channels are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis. The present study explored a possible regulatory effect of imatinib upon hERG1 K(+) channels as a means to uncover new molecular events involved in the antileukemic activity of this PTK inhibitor in CML. The results demonstrated that hERG1 was highly detected in K562 cells and primary CML cells, and down-regulated by imatinib at mRNA and protein levels. Furthermore, imatinib markedly reduced hERG currents in HEK293T-hERG cells, this effect was accompanied by inhibition of CML cell proliferation and apoptosis, as well as suppression of vascular endothelial growth factor (VEGF) secretion. Moreover, these antileukemia effects of imatinib were potentiated by E-4031, a specific hERG1 inhibitor. Together, these results provide evidence of a novel potential molecular mechanism of antileukemic activities by imatinib which, independent of targeting tyrosine kinase, highlight hERG1 K(+) channels as a therapeutic target for CML treatment.
authors.affiliation: Center for Stem Cell Research and Application, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road 1277, Wuhan 430022, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Huiyu
authors.initials: H
authors.lastname: Li
authors.forename: Kaiwei
authors.initials: K
authors.lastname: Liang
authors.forename: Yimei
authors.initials: Y
authors.lastname: Du
authors.forename: Dongmei
authors.initials: D
authors.lastname: Guo
authors.forename: Shiang
authors.initials: S
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D015536:Down-Regulation; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis* / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D010879:Piperazines; D011743:Pyrimidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate