Phosphatidylcholine-associated nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit DNA synthesis and the growth of colon cancer cells in vitro

Abstract

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.

Growth inhibition effect of DL-lysine acetylalicylate on sw480 colon carcinoma cells

“…This was consistent with a recent report which showed that NSAIDs could inhibit cell proliferation and promotes apoptosis [12] . Smith ML held a different view that aspirin could only inhibit the proliferation of sw480 colorectal cancer cells but not promote apoptosis [13] .…”

Phospholipid actions on PGHS-1 and -2 cyclooxygenase kinetics

“…The protective action of PC in this setting has been attributed to actions at the surface of gastric mucosal cells that is distinct from COX inhibition (35). However, there are indications that presentation of NSAID pre-associated with PC to cultured cells in vitro can increase the intracellular actions of the agents, including their COX-inhibitory activity (11,36). Whether this effect has any connection to the potentiation of COX inhibition by PC observed here is yet to be determined.…”

Relevance of dietary glycerophospholipids and sphingolipids to human health

“…One example is that of Dial et al [51], who supplemented colon SW-480 with soy PC and nonsteroidal anti-inflammatory drugs, inhibiting the synthesis of 2-dymethilacetales (DMA) and limiting cell proliferation. Of note, C18:0 DMA are representative of plasmalogens, a type of PL abundant in membranes [52].…”