Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib

Amanda Kirane, Jason E. Toombs, Jill E. Larsen, Katherine T. Ostapoff, Kathryn R. Meshaw, Sara Zaknoen, Rolf A. Brekken, Francis J. Burrows

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 μM and remained sufficient to completely inhibit prostaglandin E 2 production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity.

Original languageEnglish (US)
Pages (from-to)1639-1646
Number of pages8
JournalCarcinogenesis
Volume33
Issue number9
DOIs
StatePublished - Sep 1 2012

ASJC Scopus subject areas

  • Cancer Research

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    Kirane, A., Toombs, J. E., Larsen, J. E., Ostapoff, K. T., Meshaw, K. R., Zaknoen, S., Brekken, R. A., & Burrows, F. J. (2012). Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib. Carcinogenesis, 33(9), 1639-1646. https://doi.org/10.1093/carcin/bgs195