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Cyclooxygenase Inhibitors Down Regulate P-glycoprotein in Human Colorectal Caco-2 Cell Line

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Abstract

Purpose

Elevated expression of the ABC transporters P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) seems to correlate with multidrug resistance of cancer cells. In this study we investigated the effect of COX inhibitors in modulating P-gp and BCRP expression and P-gp activity in Caco-2 cells.

Methods

mRNA and protein expression of MDR1 and BCRP were evaluated by real time PCR and western blot respectively. The activity of P-gp was measured by intracellular accumulation of rhodamine123 or 3H-Digoxin.

Results

The chronic exposure of Caco-2 to indomethacin heptyl ester (indo HE) (0.4 μM) or nimesulide (10 μM) (selective COX-2 inhibitors) and naproxen (6 μM) (non selective inhibitor COX-1/COX-2) significantly decreased the expression and activity of P-gp. In contrast, the acute treatment by nimesulide and naproxen did not modify these parameters while indo HE treatment (48–72 h) caused a protein decrease and a functional inhibition of P-gp. Unexpectedly, the short-term treatment with naproxen induced an important increase of BCRP expression, but this induction was lost after long-term treatment. No modification of BCRP expression was observed after indo HE or nimesulide treatment.

Conclusion

Our observations suggest a possible down regulation of P-gp by COX inhibitors, which may enhance the accumulation of chemotherapy agents.

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Acknowledgments

This study was supported in part by grants from the university of Tishrin, Lattakia, Syrian Arabic republic.

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Authors and Affiliations

  1. Université Paris-sud XI, Faculté de Pharmacie, Laboratoire de Pharmacie Clinique, UPRES EA 2706, Tour D1, 5ème étage, 5 rue Jean-Baptist Clément, Châtenay-Malabry, 92296, France

    Afraa Zrieki, Robert Farinotti & Marion Buyse

  2. IFR 141, Université Paris-sud XI, Châtenay-Malabry, 92296, France

    Afraa Zrieki, Robert Farinotti & Marion Buyse

  3. Hôpital Pitié Salpetrière, Service de Pharmacie, Assistance Publique-Hopitaux de Paris, Paris, 75013, France

    Robert Farinotti

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  1. Afraa Zrieki
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  2. Robert Farinotti
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Correspondence to Afraa Zrieki.

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Zrieki, A., Farinotti, R. & Buyse, M. Cyclooxygenase Inhibitors Down Regulate P-glycoprotein in Human Colorectal Caco-2 Cell Line. Pharm Res 25, 1991–2001 (2008). https://doi.org/10.1007/s11095-008-9596-1

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  • DOI: https://doi.org/10.1007/s11095-008-9596-1

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