The phosphoinositide 3-kinase/Akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines

FEBS Lett. 1999 Jun 11;452(3):150-4. doi: 10.1016/s0014-5793(99)00631-6.

Abstract

Daunorubicin induces apoptosis in myeloid leukemia cells by activation of neutral sphingomyelinase and ceramide generation occurring 4-10 min after daunorubicin addition. We show here that daunorubicin is able to increase the phosphoinositide 3-kinase activity and enhance intracellular phosphoinositide 3-kinase lipid products prior to ceramide generation. Daunorubicin activates Akt, a downstream phosphoinositide 3-kinase effector. Interestingly, the phosphoinositide 3-kinase inhibitors wortmannin and LY294002 accelerate daunorubicin-induced apoptosis in U937 cells. The phosphoinositide 3-kinase/Akt pathway has been involved in cell survival following serum deprivation, tumor necrosis factor alpha, anti-Fas and UV radiations. Our results suggest that anti-tumor agents such as daunorubicin may also activate anti-apoptotic signals that could contribute to drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Androstadienes / pharmacology
  • Apoptosis
  • Ceramides / metabolism
  • Chromones / pharmacology
  • Daunorubicin / pharmacology*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Kinetics
  • Leukemia, Myeloid
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • U937 Cells
  • Wortmannin

Substances

  • Androstadienes
  • Ceramides
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Phosphatidylinositol Phosphates
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Wortmannin
  • Daunorubicin