Wang Wei, Xiao Jianbing, Adachi Masaaki, Liu Zhiyu, Zhou Jin
Department of Hematology, the First Affiliated Hospital of Harbin Medical University, Harbin, P.R. China.
Cell Physiol Biochem. 2011;28(2):199-208. doi: 10.1159/000331731. Epub 2011 Aug 16.
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+), 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+) through P(2)X(7) receptor.
4-氨基吡啶（4-AP）是一种电压门控钾通道阻滞剂，已被证实能在多种癌细胞中发挥关键的促凋亡作用。本研究旨在探讨4-AP对人急性髓系白血病（AML）细胞凋亡的影响及其潜在机制。我们发现4-AP在AML细胞系和原代培养的人AML细胞中均能抑制细胞增殖并诱导凋亡。4-AP处理后AML细胞的凋亡通过线粒体膜电位（MMP）的破坏以及半胱天冬酶3和9的激活得到进一步证实。4-AP抑制了NB(4)、HL-60和THP-1细胞中的钾离子电流。此外，4-AP使细胞内钙离子浓度（Ca(2+)）显著升高，而P(2)X(7)受体的特异性阻滞剂KN-62可抑制这种升高。KN-62也消除了4-AP诱导的凋亡。通过小干扰RNA敲低P(2)X(7)受体可阻断4-AP的作用。总之，本研究表明4-AP通过P(2)X(7)受体增加Ca(2+)来促进人AML细胞凋亡。
