The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: In vitro and in vivo studies

We have synthesized a novel derivative of indomethacin, phospho-tyrosol-indomethacin (PTI; MPI-621), and evaluated its anticancer efficacy in vitro and in vivo. PTI inhibited the growth of human colon, breast and lung cancer cell lines 6-30-fold more potently than indomethacin. In vivo, in contrast to indomethacin that was unable to inhibit colon cancer xenograft growth, PTI inhibited the growth of colon (69% at 10mg/kg/day, P < 0.01) and lung (91% at 15mg/kg/day, P < 0.01) subcutaneous cancer xenografts in immunodeficient mice, suppressing cell proliferation by 33% and inducing apoptosis by 75% (P < 0.05, for both). Regarding its pharmacokinetics in mice, after a single intraperitoneal injection of PTI, its plasma levels reached the maximum concentration (C_max = 46 μM) at 2h (T_max) and became undetectable at 4h. Indomethacin is the major metabolite of PTI, with plasma C_max = 378 μM and T_max = 2.5h; it became undetectable 24h postadministration. The cellular uptake of PTI (50-200 μM) at 6h was about 200-fold greater than that of indomethacin. Regarding its safety, PTI had no significant genotoxicity, showed less gastrointestinal toxicity than indomethacin and presented no cardiac toxicity. Mechanistically, PTI suppressed prostaglandin E₂ production in A549 human lung cancer cells and strongly inhibited nuclear factor-κB activation in A549 xenografts. These findings indicate that PTI merits further evaluation as an anticancer agent.