Abstract
The cytochrome P450 epoxygenase, CYP2J2, converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs). We found recently that this enzyme is dramatically up-regulated in a variety of established human carcinoma cell lines and in human cancerous tissue and promotes the neoplastic phenotype. In the present study, we tested the hypothesis that specific inhibitors of CYP2J2 related to the drug terfenadine are effective antitumor agents. Four of these inhibitors (compounds 4, 5, 11, and 26) were tested for effectiveness in vitro and in vivo. In Tca-8113 cells, the CYP2J2 inhibitors decreased EET production by approximately 60%, whereas they had no effect on CYP2J2 mRNA or protein expression. Compound 26 inhibited the proliferation of human tumor cells, reduced their ability to adhere, invade, and migrate, and attenuated activation of epithelial growth factor receptor signal and kinases and phosphatidylinositol 3 kinase/Akt pathways. Inhibition of CYP2J2 also significantly potentiated human tumor cell apoptosis and caused a corresponding increase in caspase-3 activity and change in expression of apoptosis-related proteins Bax and Bcl-2. In murine xenograft models using MDA-MB-435 cells, treatment with compound 26 significantly repressed tumor growth, decreased lung metastasis, and was associated with increased expression of the anticancer genes CD82 and nm23, without causing toxicity. These data suggest that CYP2J2 inhibitors hold significant promise for use in treatment of neoplastic diseases.
Footnotes
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This work was supported in part by the China Natural Science Foundation Committee [Grants 30540087, 30430320]; the International Collaboration Project [Grant 2005DFA30880]; the 973 Program [Grants 2007CB512004, 2002CB513107]; and by the Intramural Research program of the National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01 ES025034].
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C.C., G.L., and W.L. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.152017.
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ABBREVIATIONS: P450, cytochrome P450; EET, epoxyeicosatrienoic acid; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; RT, reverse transcriptase; PCR, polymerase chain reaction; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; EGFR, epithelial growth factor receptor; PI3, phosphatidylinositol 3; HEK, human embryonic kidney; BAEC, bovine aortic endothelial cell; C26, compound 26; compound 11, 1-(4-bromophenyl)-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-butanone; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; 14,15-DHET, 14,15-dihydroxyeicosatrienoic acid; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay; 20-HETE, 20-hydroxyeicosatetraenoic acid; HPF, high-power field; FITC, fluorescein isothiocyanate; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material. - Received February 10, 2009.
- Accepted March 12, 2009.
- U.S. Government work not protected by U.S. copyright
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Selective Inhibitors of CYP2J2 Related to Terfenadine Exhibit Strong Activity against Human Cancers in Vitro and in Vivo
