3-bromopyruvate as a Promising Treatment for Hematological Cancer

Abstract

Many biological differences exist between cancer cells and normal cells that can act as potential targets in targeted cancer therapy. Hematological cancers e.g. lymphoma, leukemia and myeloma exhibit drug-resistance that ultimately results in deteriorated patients' conditions and high mortality rates. Resistance of hematological malignancy to conventional chemotherapy is attributed in part to upregulation of glucose oxidation (glycolysis) genes evidenced by gaining a promising chemosensitization effect upon adding a glycolysis inhibitor to chemotherapeutics. The promising anticancer agent 3-bromopyruvate (3BP) is a structural analog of both pyruvate and lactate. 3BP was reported to antagonize the Warburg effect (malignant phenotype where cancer cells utilize cytoplasmic glucose oxidation to produce ATP and lactate even in the presence of oxygen without making benefit of the generous ATP provision from glucose oxidation via mitochondrial pathways). Warburg effect deprives cancer cells from the high energetic yield achieved through utilizing mitochondrial pathways. 3BP is a promising antiglycolytic agent that targets major glycolysis enzymes (hexokinase II and glyceraldehyde-3-phosphate dehydrogenase. In this article, 3BP promising anticancer effects in treating lymphoma, leukemia and myeloma are discussed in addition to the mode of inhibition of Warburg effect using 3BP. In conclusion, 3BP is a promising anticancer drug (that will be more powerful upon proper pharmaceutical formulations) for treating hematological malignancies. 3BP is advisable to be included in treatment protocols in hematological cancers as a chemosensitizer or as a sole anticancer agent.

Hexokinase II inhibition by 3-bromopyruvate sensitizes myeloid leukemic cells K-562 to anti-leukemic drug, daunorubicin

“…The ROS generation in K-562 cells was four-fold high as compared with THP-1 cells suggestive of K-562 is an aggressive Warburg phenotype [43]. We hypothesized that inhibition of glycolysis and HK-II mitochondrial association using 3-BP, a pyruvate analog and a potent inhibitor of HK-II can weaken the aggressiveness of Warburg phenotype K-562 cells and make it susceptible to anthracycline anticancer agent, DNR [23,44]. We found that 3-BP synergistically sensitized and increased the susceptibility of K-562 cells to 10 nM DNR, by two-fold (29–58% and SI ≥ 1, Figure 2C).…”

“…However, data presented here suggest that the combined DNR and 3-BP treatment leads to profound accumulation of cells in both S phase and G 2 /M phase resulting in significantly higher growth delay. It has been found that mitochondrial dissociation of HK-II is the consequence of 3-BP induced covalent modification followed by the commencement of apoptosis in cancer cells [23,44]. Therefore we examined the correlation between 3-BP induced HK-II dissociation from mitochondria and apoptosis in K-562 cells.…”