title: The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies.
abstract: 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 (Cmax = 46 μM) at 2h (Tmax) and became undetectable at 4h. Indomethacin is the major metabolite of PTI, with plasma Cmax = 378 μM and Tmax = 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.
authors: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794-8175, USA.
authors: Dingying
authors: D
authors: Zhou
authors: Ioannis
authors: I
authors: Papayannis
authors: Gerardo G
authors: GG
authors: Mackenzie
authors: Ninche
authors: N
authors: Alston
authors: Nengtai
authors: N
authors: Ouyang
authors: Liqun
authors: L
authors: Huang
authors: Ting
authors: T
authors: Nie
authors: Chi C
authors: CC
authors: Wong
authors: Basil
authors: B
authors: Rigas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects; D009368:Neoplasm Transplantation; D010755:Organophosphates / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D010755:Organophosphates; C581098:phospho-tyrosol-indomethacin; D015232:Dinoprostone; D007213:Indomethacin