The apoptotic effect of HA14-1, a Bcl-2-interacting small molecular compound, requires Bax translocation and is enhanced by PK11195.
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.
Chen
Jun
J
Huntsman Cancer Institute, Section of Oncology, Department of Medicine, University of Utah, 2000 Circle of Hope, Suite 5244, Salt Lake City, UT 84112, USA.
Freeman
Angela
A
Liu
Jihua
J
Dai
Qiang
Q
Lee
Ruey-min
RM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002474:Cell-Free System; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013347:Subcellular Fractions; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; C494827:Bax protein, mouse; D001578:Benzopyrans; D061945:Caspase Inhibitors; D004396:Coloring Agents; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D013844:Thiazoles; D051028:bcl-2-Associated X Protein; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D020169:Caspases; C022616:thiazolyl blue; C037850:PK 11195