The apoptotic effect of HA14-1, a Bcl-2-interacting small molecular compound, requires Bax translocation and is enhanced by PK11195

Mol Cancer Ther. 2002 Oct;1(12):961-7.


HA14-1 is a small molecular compound that was identified based on the structure of Bcl-2. HA14-1 interacts with Bcl-2 and inhibits the antiapoptotic effect of Bcl-2. We investigated the mechanism of HA14-1-induced apoptosis and found that HA14-1 induces translocation of Bax from cytosols to the mitochondria. Cells deficient in Bax were much more resistant to HA14-1-induced apoptosis, suggesting that Bax is required for this process. A pan-caspase inhibitor failed to inhibit the apoptotic effect of HA14-1, indicating that this is through a caspase-independent pathway. To eliminate the effect of cytosolic Bax, we incubated cell-free mitochondria with HA14-1 to study its effect on cytochrome c release. HA14-1 was ineffective in causing cytochrome c release from the purified mitochondria. However, the combination of HA14-1 and PK11195, an antagonist of peripheral benzodiazepine receptor of the mitochondria, enhanced the cytochrome c release by HA14-1. The combination of PK11195 and HA14-1 could therefore serve as a potentially useful approach to enhance apoptosis in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • Benzopyrans / pharmacology*
  • Blotting, Western
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Survival
  • Cell-Free System
  • Cells, Cultured
  • Coloring Agents / pharmacology
  • Cytochrome c Group / metabolism
  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • HL-60 Cells
  • Humans
  • In Situ Nick-End Labeling
  • Isoquinolines / pharmacology*
  • Mice
  • Microscopy, Fluorescence
  • Mitochondria / drug effects
  • Nitriles / pharmacology*
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Subcellular Fractions
  • Tetrazolium Salts / pharmacology
  • Thiazoles / pharmacology
  • Time Factors
  • bcl-2-Associated X Protein


  • Antineoplastic Agents
  • BAX protein, human
  • Bax protein, mouse
  • Benzopyrans
  • Caspase Inhibitors
  • Coloring Agents
  • Cytochrome c Group
  • Enzyme Inhibitors
  • Isoquinolines
  • Nitriles
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tetrazolium Salts
  • Thiazoles
  • bcl-2-Associated X Protein
  • ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
  • Caspases
  • thiazolyl blue
  • PK 11195