title: 4-aminopyridine induces apoptosis of human acute myeloid leukemia cells via increasing [Ca2+]i through P2X7 receptor pathway.
abstract: 4-AP, a voltage-gated potassium channel blocker, was identified to exert critical pro-apoptotic properties in various types of cancer cells. The present study aims to explore the effect of 4-AP on the apoptosis of human AML cells and the underlying mechanism. We found 4-AP inhibited the proliferation and induces apoptosis in both AML cell lines and primary cultured human AML cells. The apoptosis of AML cells after 4-AP treatment was further confirmed by the disruption of mitochondrial membrane potential (MMP) and activation of caspase 3 and 9. 4-AP inhibited Kv currents in NB(4), HL-60 and THP-1 cells. Furthermore, 4-AP induced significant increment in [Ca(2+)](i), which were inhibited by KN-62, a specific blocker of P(2)X(7) receptors. KN-62 also abrogated 4-AP induced apoptosis. Knockdown of P(2)X(7) receptor by small interfering RNA blocked the effect of 4-AP. Conclusively, this study indicated that 4-AP promotes apoptosis in human AML cells via increasing [Ca(2+)](i) through P(2)X(7) receptor.
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Harbin Medical University, Harbin, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jianbing
authors.initials: J
authors.lastname: Xiao
authors.forename: Masaaki
authors.initials: M
authors.lastname: Adachi
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Liu
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D015761:4-Aminopyridine / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D015220:Calcium Channels; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D058920:Purinergic P2X Receptor Antagonists; D034741:RNA, Small Interfering; D058486:Receptors, Purinergic P2X7; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015761:4-Aminopyridine; D053148:Caspase 3; D053453:Caspase 9; D002118:Calcium