combination of sulindac and dichloroacetate kills cancer cells via oxidative damage二氯醋酸苏灵大和杀死癌细胞通过氧化损伤.pdf

Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage 1,2 . 1. 1,2 1 Kasirajan Ayyanathan * , Shailaja Kesaraju , Ken Dawson-Scully , Herbert Weissbach 1 Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University, Jupiter, Florida, United States of America, 2 Department of Biological Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, Florida, United States of America Abstract Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown