Initiation of apoptosis and autophagy by the Bcl-2 antagonist HA14-1

Cancer Lett. 2007 May 8;249(2):294-9. doi: 10.1016/j.canlet.2006.09.009. Epub 2006 Oct 19.

Abstract

L1210 murine leukemia cells exposed to an LD(90) concentration of the Bcl-2/Bcl-x(L) antagonist HA14-1 rapidly undergo apoptosis but also develop numerous intracellular vacuoles with double membranes, exhibit enhanced labeling by monodansylcadaverine, and convert the cytosolic protein LC3-I to LC3-II. These are hallmarks of autophagy. Autophagic vacuoles develop rapidly, preceding the appearance of an apoptotic nuclear morphology and can be observed in both non-apoptotic and apoptotic cells. Inhibition of autophagy by the PI 3-kinase inhibitor wortmannin promoted apoptosis; conversely inhibition of caspase-3/7 with zDEVD-fmk promoted autophagy. Neither process was dependent on calcium translocation. These results indicate that pharmacological suppression of Bcl-2 function can mimic the induction of autophagy that can occur following the down-regulation of Bcl-2 expression by molecular approaches.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Benzopyrans / pharmacology*
  • Cell Line, Tumor
  • Chelating Agents / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Microscopy, Electron
  • Nitriles / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*

Substances

  • Benzopyrans
  • Chelating Agents
  • Nitriles
  • Proto-Oncogene Proteins c-bcl-2
  • ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Egtazic Acid