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

16 Citations (Scopus)

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 2012

Fingerprint

Epithelial-Mesenchymal Transition
Cyclooxygenase 2
Neoplasms
HT29 Cells
Blood Vessels
Carcinoma
Cyclooxygenase 2 Inhibitors
Vimentin
Cadherins
Growth
Prostaglandins E
apricoxib
Non-Small Cell Lung Carcinoma
Pharmaceutical Preparations
Antineoplastic Agents
Colorectal Neoplasms
Colon
Up-Regulation
Pharmacokinetics
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research

Cite this

Kirane, A., Toombs, J. E., Larsen, J. E., Ostapoff, K. T., Meshaw, K. R., Zaknoen, S., ... 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

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.; Burrows, Francis J.

In: Carcinogenesis, Vol. 33, No. 9, 09.2012, p. 1639-1646.

Research output: Contribution to journalArticle

Kirane, A, Toombs, JE, Larsen, JE, Ostapoff, KT, Meshaw, KR, Zaknoen, S, Brekken, RA & Burrows, FJ 2012, 'Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib', Carcinogenesis, vol. 33, no. 9, pp. 1639-1646. https://doi.org/10.1093/carcin/bgs195
Kirane A, Toombs JE, Larsen JE, Ostapoff KT, Meshaw KR, Zaknoen S et al. Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib. Carcinogenesis. 2012 Sep;33(9):1639-1646. https://doi.org/10.1093/carcin/bgs195
Kirane, Amanda ; Toombs, Jason E. ; Larsen, Jill E. ; Ostapoff, Katherine T. ; Meshaw, Kathryn R. ; Zaknoen, Sara ; Brekken, Rolf A. ; Burrows, Francis J. / Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib. In: Carcinogenesis. 2012 ; Vol. 33, No. 9. pp. 1639-1646.
@article{3ec35ca85cad45749f31119339f60da3,
title = "Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib",
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.",
author = "Amanda Kirane and Toombs, {Jason E.} and Larsen, {Jill E.} and Ostapoff, {Katherine T.} and Meshaw, {Kathryn R.} and Sara Zaknoen and Brekken, {Rolf A.} and Burrows, {Francis J.}",
year = "2012",
month = "9",
doi = "10.1093/carcin/bgs195",
language = "English (US)",
volume = "33",
pages = "1639--1646",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib

AU - Kirane, Amanda

AU - Toombs, Jason E.

AU - Larsen, Jill E.

AU - Ostapoff, Katherine T.

AU - Meshaw, Kathryn R.

AU - Zaknoen, Sara

AU - Brekken, Rolf A.

AU - Burrows, Francis J.

PY - 2012/9

Y1 - 2012/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84865539644&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865539644&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgs195

DO - 10.1093/carcin/bgs195

M3 - Article

VL - 33

SP - 1639

EP - 1646

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 9

ER -