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

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.

• Authors: David Kessel, John J Reiners Jr
• Journal: Cancer letters (Cancer Lett) Vol. 249 Issue 2 Pg. 294-9 (May 08 2007) ISSN: 0304-3835 [Print] Ireland
• PMID: 17055152 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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