Abstract
BackgroundSulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID) that affects prostaglandin production by inhibiting cyclooxygenases (COX) 1 and 2. Sulindac has also been of interest for more than decade as a chemopreventive for adenomatous colorectal polyps and colon cancer.Principal FindingsPretreatment of human colon and lung cancer cells with sulindac enhances killing by an oxidizing agent such as tert-butyl hydroperoxide (TBHP) or hydrogen peroxide. This effect does not involve cyclooxygenase (COX) inhibition. However, under the conditions used, there is a significant increase in reactive oxygen species (ROS) within the cancer cells and a loss of mitochondrial membrane potential, suggesting that cell death is due to apoptosis, which was confirmed by Tunel assay. In contrast, this enhanced killing was not observed with normal lung or colon cells.SignificanceThese results indicate that normal and cancer cells handle oxidative stress in different ways and sulindac can enhance this difference. The combination of sulindac and an oxidizing agent could have therapeutic value.
Highlights
Sulindac was one of the early non-steroidal anti-inflammatory drugs (NSAIDs), which affect prostaglandin production by inhibiting cyclooxygenases (COX) 1 and 2 [1]
Viability of lung cancer cells pretreated with sulindac was reduced by greater than 80% following incubation for 2 hr with 240 mM tert-butyl hydroperoxide (TBHP) when compared to control cells that were not pretreated with sulindac (Figure 1A)
Similar responses to TBHP were observed with sulindac treated colon cancer cells (Figure 1B), a higher concentration of TBHP was required for significant killing of the colon cancer cells
Summary
Sulindac was one of the early non-steroidal anti-inflammatory drugs (NSAIDs), which affect prostaglandin production by inhibiting cyclooxygenases (COX) 1 and 2 [1]. For more than a decade, sulindac has been of interest as a chemopreventive treatment for adenomatous colorectal polyps and colon cancer [2,3,4,5], especially in patients with familial adenomatous polyposis [6]. We have previously shown that conversion of sulindac to sulindac sulfide can be catalyzed by MsrA, a member of the methionine sulfoxide reductase (Msr) family of enzymes [20]. Sulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID) that affects prostaglandin production by inhibiting cyclooxygenases (COX) 1 and 2. Sulindac has been of interest for more than decade as a chemopreventive for adenomatous colorectal polyps and colon cancer
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