Chemoprevention with phosphatidylcholine non-steroidal anti-inflammatory drugs in vivo and in vitro

Abstract

The chemopreventive activity of non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, has been well demonstrated in preclinical and clinical studies. However, the primary side effect from this class of drug is gastrointestinal (GI) bleeding, which has limited the widespread use of NSAIDs for the prevention of cancer. The development of GI-safer NSAIDs, which are associated with phosphatidylcholine (PC) may provide a solution to this therapeutic problem. In the present study, the efficacy of two NSAIDs, aspirin and indomethacin, were compared using murine colon cancer cell line MC-26. Each NSAID was assessed alone and in combination with PC, using in vitro and in vivo systems. The results reveal that the PC-associated NSAIDs had a significantly higher degree of protection against cancer cell growth compared with the unmodified NSAIDs. It was also observed that Aspirin-PC and Indomethacin-PC prevented the metastatic spread of cancer cells in a syngeneic mouse model. These results support the potential use of PC-NSAIDs for the chemoprevention of colorectal cancer.

Keywords: aspirin; chemoprevention; colorectal cancer; indomethacin; non-steroidal anti-inflammatory drug.

Figure 1.

Chemical structures of aspirin, indomethacin and soy phosphatidylcholine.

Figure 2.

In vitro effects of test drugs on MC-26 colon cancer cells. Test drugs were incubated with cells at (A and C) 0–1 mmol/l for aspirin and Aspirin-PC or (B and D) 0–50 mmol/l for indomethacin and Indomethacin-PC. Cell growth was analyzed by (A and B) MTT assay and (C and D) PGE₂ in the medium by ELISA. All experiments were repeated three times and significant differences are indicated.

Figure 3.

Effect of test drugs on MC-26 cancer cell implantation mouse model system. Immediately after cancer cell inoculation into the splenic capsule, the mice were randomly grouped and administered with saline (vehicle), aspirin, Aspirin-PC, indomethacin, or Indomethacin-PC for 28 days, daily at the following NSAID doses: 20 mg/kg ASA, 20 mg/kg ASA + 20 mg/kg PC, 2 mg/kg Indo, and 2 mg/kg Indo + 4 mg/kg PC, respectively. A non-cancer group was also included as control. Values are: (A) spleen weight; (B) liver metastases; (C) serum TXB₂; and (D) spleen PGE₂. *P<0.05 vs. saline group.