Phosphatidylcholine-associated nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit DNA synthesis and the growth of colon cancer cells in vitro
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The use of NSAIDs or COX-2 inhibitors for chemoprevention of colorectal cancer has been suggested for patients at high risk for this disease. However, the gastrointestinal side effects of traditional NSAIDs which consist of bleeding and ulceration, and the cardiovascular effects of COX-2 inhibitors may limit their usefulness. In preclinical studies, our laboratory has shown that the addition of phosphatidylcholine (PC) to the NSAIDs aspirin (ASA) or ibuprofen (IBU) results in a NSAID–PC with fewer GI side effects and also maintained or enhanced analgesic, anti-pyretic and anti-inflammatory efficacy over the unmodified NSAID. Because NSAID–PCs have not been tested for anti-cancer activity, in the present study, ASA–PC and IBU–PC were tested on the SW-480 human colon cancer cell line. SW-480 cells were incubated in media containing 1–5 mM NSAID or NSAID–PC for 2 days. Measurements were made of cell number, cell proliferation (DNA synthesis), and manner of cell death (necrosis and apoptosis). ASA and IBU reduced cell number in a dose-dependent manner with IBU showing a greater potency than ASA. The association of PC to the NSAID resulted in greater reductions of cell number for both NSAIDs. Furthermore, the NSAID–PC formulation had significantly greater efficacy and potency to inhibit cellular DNA synthesis than the unmodified NSAID. PC alone at the doses and times used had no effect on cell number in this cell line, but did have a small effect to reduce DNA synthesis. None of the drugs had a clear effect on cell death by necrosis. Only IBU and IBU–PC caused cell death by apoptosis in SW-480 cells. We conclude that NSAID–PCs have activity to impede the growth of colon cancer cells in vitro, which is due, in major part, to a marked reduction in DNA synthetic activity of these cells. This growth inhibitory effect appears to be independent of COX-2 activity, since it is known that SW-480 cells do not have this inducible COX isoform. Due to its greater efficacy in this model system, IBU–PC should be further evaluated as a chemopreventive agent that is safer for the GI tract than unmodified NSAID.
KeywordsNSAID Phosphatidylcholine Colon cancer Aspirin Ibuprofen
This project was supported in part by PHS DK56338 which funds the Texas Gulf Coast Digestive Diseases Center.
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