The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies.
The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies.
复制标题
磷酸酪醇吲哚美辛 (MPI-621)（一种新型吲哚美辛磷酸衍生物）的抗癌作用：体外和体内研究。
DOI：
10.1093/carcin/bgs394
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发表时间：
2013
期刊：
影响因子：
4.7
通讯作者：
Rigas,Basil
中科院分区：
文献类型：
--
作者：
Zhou,Dingying;Papayannis,Ioannis;Mackenzie,GerardoG;Alston,Ninche;Ouyang,Nengtai;Huang,Liqun;Nie,Ting;Wong,ChiC;Rigas,Basil
We have synthesized a novel derivative of indomethacin, phospho-tyrosol-indomethacin (PTI; MPI-621), and evaluated its anticancer efficacyin vitroandin 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 (Cmax= 46 μM) at 2h (Tmax) and became undetectable at 4h. Indomethacin is the major metabolite of PTI, with plasmaCmax= 378 μM andTmax= 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 E2production 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.
