Bongkrekic acid inhibits 2-deoxygulcose-induced apoptosis, leading to enhanced cytotoxicity and necrotic cell death

Targeting glucose metabolism using the glycolysis inhibitor, 2-deoxyglucose (2-DG), is a promising therapeutic strategy for cancers characterized by elevated glucose requirements. Although clinical studies have revealed that effective doses cause side effects, research on combination therapies is ongoing. 2-DG inhibits not only glycolysis but also glycosylation of newly synthesized proteins and disturbs protein folding, resulting in endoplasmic reticulum (ER) stress-mediated apoptosis. Meanwhile, bongkrekic acid (BKA) is a toxic compound, which has been reported to inhibit ADP/ATP exchange in the mitochondria and suppress apoptosis by interfering with cytochrome c release from the mitochondria. Herein, 100 µM BKA inhibited 2-DG-induced apoptosis but showed enhanced cytotoxicity in the 4T1 murine breast cancer cell line, resulting in necrotic cell death. Surprisingly, BKA did not suppress 2-DG-induced cytochrome c release from the mitochondria, but effectively inhibited caspase activation. Furthermore, BKA did not suppress the upregulation of ER stress marker C/EBP homologous protein but suppressed autophagy flux. Our findings suggest an alternative treatment for cancer using BKA in combination with 2-DG.