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

Kirane, Amanda, Toombs, Jason E., Larsen, Jill E., Ostapoff, Katherine T., Meshaw, Kathryn R., Zaknoen, Sara, Brekken, Rolf A. and Burrows, Francis J. (2012) Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib. Carcinogenesis, 33 9: 1639-1646. doi:10.1093/carcin/bgs195


Author Kirane, Amanda
Toombs, Jason E.
Larsen, Jill E.
Ostapoff, Katherine T.
Meshaw, Kathryn R.
Zaknoen, Sara
Brekken, Rolf A.
Burrows, Francis J.
Title Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib
Journal name Carcinogenesis   Check publisher's open access policy
ISSN 0143-3334
1460-2180
Publication date 2012-09
Sub-type Article (original research)
DOI 10.1093/carcin/bgs195
Volume 33
Issue 9
Start page 1639
End page 1646
Total pages 8
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Fri, 04 Oct 2013, 13:46:56 EST by Jill Larsen on behalf of School of Medicine