Cancer Cell Signaling

Sulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID), which has also been shown to have anti-cancer activity [1]-[6]. Recent studies from our laboratory have demonstrated that RKO, A549 and SCC25 cancer cell lines exhibited sensitivity towards a combination of sulindac and an oxidizing agent, such as TBHP or H2O2 [7]. The data indicated that the sulindac effect was not related to its NSAID activity but that sulindac made cancer cells more sensitive to oxidative stress resulting in mitochondrial dysfunction and loss of viability. In contrast, normal cells did not show enhanced killing under similar conditions [7]. 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]-[14]. Although 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]. In fact, ROS have been implicated in the studies using sulindac in combination with arsenic trioxide, bortezomib and SAHA [10], [12], [14].