Myeloperoxidase-mediated bio-activation of NSAIDs in leukemia cells: Potential selective cytotoxicity

Abstract

Several lines of evidence have pointed to the potential benefit of anti-inflammatory drugs (NSAIDs) in cancer therapy due to the well-established correlation between cancer and chronic inflammation. Acute myeloid leukemia (AML) cells overexpress myeloperoxidase (MPO), which has been studied for its ability to bio-activate xenobiotics into reactive species with little research done on its potential to be a target in treating leukemic cells. Our main hypothesis is that MPO bio-activation of NSAIDs produce pro-oxidant species that will cause oxidative damage and induce leukemic cell death. To test our hypothesis, a number of biochemical and in vitro studies were conducted. In the first two studies, we included four different NSAIDs, namely diclofenac, naproxen, indomethacin and mefenamic acid and we also included their hepatic metabolites and chemical analogues for comparative purposes. We found that MPO was capable of oxidizing certain NSAIDs and their metabolites/analogues to reactive species, which have cytotoxic potential to HL-60 leukemia cell lines through oxidizing GSH and dropping mitochondrial membrane potential and inducing leukemic cell death. Interestingly, even a few structural changes between metabolites and the parent NSAIDs exhibited significant differences in the reactivity of the results species and in their cytotoxic potential in vitro. These studies suggest a potential novel approach of modulating leukemia cells oxidative balance and viability by taking advantage of the high expression of MPO and its oxidizing capacity of NSAIDs. Further studies are needed to evaluate the role of MPO expression levels in leukemia cells’ response to NSAIDs by using leukemia cells with different levels of MPO expression and to investigate the effect of combining the clinically used chemotherapy agents with NSAIDs on the potency of the former in eradicating leukemia cells. In our third study, the cell culture pH indicator, phenol red, was found to be oxidized by MPO into free radical species as well as halogenated metabolites that depleted HL-60 cells’ glutathione but did not significantly affect cell viability. Phenol red is a phenolic compound that was structurally similar to hydroxylated NSAID metabolites. The latter suggests potential interference of phenol red-containing cell culture media with oxidative stress studies done in MPO expressing cell lines, which mandates cautious selection of cell culture media depending on the nature of the studies.