The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin

In vitro and in vivo studies

Dingying Zhou, Ioannis Papayannis, Gerardo Mackenzie, Ninche Alston, Nengtai Ouyang, Liqun Huang, Ting Nie, Chi C. Wong, Basil Rigas

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)943-951
Number of pages9
JournalCarcinogenesis
Volume34
Issue number4
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

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Indomethacin
Heterografts
Colonic Neoplasms
Lung Neoplasms
Growth
Intraperitoneal Injections
Dinoprostone
Antineoplastic Agents
In Vitro Techniques
phospho-tyrosol-indomethacin
Colon
Pharmacokinetics
Cell Proliferation
Apoptosis
Breast Neoplasms
Safety
Cell Line
Lung
Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin : In vitro and in vivo studies. / Zhou, Dingying; Papayannis, Ioannis; Mackenzie, Gerardo; Alston, Ninche; Ouyang, Nengtai; Huang, Liqun; Nie, Ting; Wong, Chi C.; Rigas, Basil.

In: Carcinogenesis, Vol. 34, No. 4, 01.04.2013, p. 943-951.

Research output: Contribution to journalArticle

Zhou, Dingying ; Papayannis, Ioannis ; Mackenzie, Gerardo ; Alston, Ninche ; Ouyang, Nengtai ; Huang, Liqun ; Nie, Ting ; Wong, Chi C. ; Rigas, Basil. / The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin : In vitro and in vivo studies. In: Carcinogenesis. 2013 ; Vol. 34, No. 4. pp. 943-951.
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