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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 that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy.
Highlights
Sulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID), which has been shown to have anti-cancer activity [1,2,3,4,5,6]
A sulindac dose response curve under these conditions indicated that A549 and SCC25 cancer cells can tolerate a maximum concentration of 500 mM and 100 mM of sulindac, respectively, without exhibiting any significant killing, and these concentrations were used in all the studies
The present study is an extension of our previous work, which demonstrated that sulindac made cancer cells, but not normal cells, more sensitive to oxidative stress [7]
Summary
Sulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID), which has been shown to have anti-cancer activity [1,2,3,4,5,6]. In the past 10 years there have been scattered reports of enhanced cancer killing using sulindac in combination with a variety of compounds including arsenic trioxide, bortezomib, difluoromethylornithine (DFMO) and suberoylanilide hydroxamic acid (SAHA) [8,9,10,11,12,13,14]. These compounds have different sites of action, a common mechanism for the sulindac/ drug combination enhanced killing might involve oxidative damage, as was clearly demonstrated in our previous studies using sulindac and an oxidizing agent [7,15]. ROS have been implicated in the studies using sulindac in combination with arsenic trioxide, bortezomib and SAHA [10,12,14]
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