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 NB₄, HL-60 and THP-1 cells. Furthermore, 4-AP induced significant increment in [Ca²⁺]_i, which were inhibited by KN-62, a specific blocker of P₂X₇ receptors. KN-62 also abrogated 4-AP induced apoptosis. Knockdown of P₂X₇ 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 [Ca²⁺]_i through P₂X₇ receptor.