4-aminopyridine induces apoptosis of human acute myeloid leukemia cells via increasing [Ca2+]i through P2X7 receptor pathway

Cell Physiol Biochem. 2011;28(2):199-208. doi: 10.1159/000331731. Epub 2011 Aug 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • 4-Aminopyridine / pharmacology*
  • Apoptosis / drug effects*
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Membrane Potential, Mitochondrial / drug effects
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels, Voltage-Gated / antagonists & inhibitors
  • Potassium Channels, Voltage-Gated / metabolism
  • Potassium Channels, Voltage-Gated / physiology
  • Purinergic P2X Receptor Antagonists / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Purinergic P2X7 / chemistry
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / metabolism*
  • Tumor Cells, Cultured

Substances

  • Calcium Channels
  • Potassium Channel Blockers
  • Potassium Channels, Voltage-Gated
  • Purinergic P2X Receptor Antagonists
  • RNA, Small Interfering
  • Receptors, Purinergic P2X7
  • KN 62
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • 4-Aminopyridine
  • Caspase 3
  • Caspase 9
  • Calcium