Cyclooxygenase Inhibitors Down Regulate P-glycoprotein in Human Colorectal Caco-2 Cell Line
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
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.
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.
Our observations suggest a possible down regulation of P-gp by COX inhibitors, which may enhance the accumulation of chemotherapy agents.
- V. Lingand, and L. H. Thompson. Reduced permeability in CHO cells as a mechanism of resistance to colchicine. J. Cell. Physiol. 83:103–116 (1974). CrossRef
- F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA. 84:7735–7738 (1987). CrossRef
- M. F. Fromm. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int. J. Clin. Pharmacol. Ther. 38:69–74 (2000).
- W. L. Smithand, and D. L. Dewitt. Prostaglandin endoperoxide H synthases-1 and -2. Adv. Immunol. 62:167–215 (1996). CrossRef
- G. P. O'Neilland, and A. W. Ford-Hutchinson. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett. 330:156–60 (1993).
- C. C. Chan, S. Boyce, C. Brideau, A. W. Ford-Hutchinson, R. Gordon, D. Guay, R. G. Hill, C. S. Li, J. Mancini, M. Penneton et al. Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: a novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach. J. Pharmacol. Exp. Ther. 274:1531–1537 (1995).
- T. Tanioka, Y. Nakatani, T. Kobayashi, M. Tsujimoto, S. Oh-ishi, M. Murakami, and I. Kudo. Regulation of cytosolic prostaglandin E2 synthase by 90-kDa heat shock protein. Biochem. Biophys. Res. Commun. 303:1018–1023 (2003). CrossRef
- R. N. Dubois, S. B. Abramson, L. Crofford, R. A. Gupta, L. S. Simon, L. B. Van De Putte, and P. E. Lipsky. Cyclooxygenase in biology and disease. FASEB J. 12:1063–1073 (1998).
- C. E. Trebino, J. L. Stock, C. P. Gibbons, B. M. Naiman, T. S. Wachtmann, J. P. Umland, K. Pandher, J. M. Lapointe, S. Saha, M. L. Roach, D. Carter, N. A. Thomas, B. A. Durtschi, J. D. McNeish, J. E. Hambor, P. J. Jakobsson, T. J. Carty, J. R. Perez, and L. P. Audoly. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc. Natl. Acad. Sci. USA. 100:9044–9049 (2003). CrossRef
- C. Patrono, P. Patrignani, and L. A. Garcia Rodriguez. Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J. Clin. Invest. 108:7–13 (2001).
- J. A. Mitchelland, and T. D. Warner. Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. Br. J. Pharmacol. 128:1121–32 (1999). CrossRef
- I. I. Singer II, D. W. Kawka, S. Schloemann, T. Tessner, T. Riehl, and W. F. Stenson. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology 115:297–306 (1998).
- C. E. Eberhart, R. J. Coffey, A. Radhika, F. M. Giardiello, S. Ferrenbach, and R. N. DuBois. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 107:1183–8 (1994).
- H. Sheng, J. Shao, J. D. Morrow, R. D. Beauchamp, and R. N. DuBois. Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 58:362–366 (1998).
- M. Tsujii, S. Kawano, S. Tsuji, H. Sawaoka, M. Hori, and R. N. DuBois. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 93:705–716 (1998). CrossRef
- N. Arber, C. J. Eagle, J. Spicak, I. Racz, P. Dite, J. Hajer, M. Zavoral, M. J. Lechuga, P. Gerletti, J. Tang, R. B. Rosenstein, K. Macdonald, P. Bhadra, R. Fowler, J. Wittes, A. G. Zauber, S. D. Solomon, and B. Levin. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med. 355:885–95 (2006). CrossRef
- Y. Goldberg, Nassif, II, A. Pittas, L. L. Tsai, B. D. Dynlacht, B. Rigas, and S. J. Shiff. The anti-proliferative effect of sulindac and sulindac sulfide on HT-29 colon cancer cells: alterations in tumor suppressor and cell cycle-regulatory proteins. Oncogene 12:893–901 (1996).
- J. Shao, T. Fujiwara, Y. Kadowaki, T. Fukazawa, T. Waku, T. Itoshima, T. Yamatsuji, M. Nishizaki, J. A. Roth, and N. Tanaka. Overexpression of the wild-type p53 gene inhibits NF-kappaB activity and synergizes with aspirin to induce apoptosis in human colon cancer cells. Oncogene. 19:726–36 (2000). CrossRef
- S. Hashitani, M. Urade, N. Nishimura, T. Maeda, K. Takaoka, K. Noguchi, and K. Sakurai. Apoptosis induction and enhancement of cytotoxicity of anticancer drugs by celecoxib, a selective cyclooxygenase-2 inhibitor, in human head and neck carcinoma cell lines. Int. J. Oncol. 23:665–672 (2003).
- J. L. Masferrer, K. M. Leahy, A. T. Koki, B. S. Zweifel, S. L. Settle, B. M. Woerner, D. A. Edwards, A. G. Flickinger, R. J. Moore, and K. Seibert. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 60:1306–1311 (2000).
- M. K. Jones, H. Wang, B. M. Peskar, E. Levin, R. M. Itani, I. J. Sarfeh, and A. S. Tarnawski. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat. Med. 5:1418–1423 (1999). CrossRef
- V. A. Patel, M. J. Dunn, and A. Sorokin. Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2. J. Biol. Chem. 277:38915–38920 (2002). CrossRef
- M. C. Zatelli, A. Luchin, D. Piccin, F. Tagliati, A. Bottoni, C. Vignali, M. Bondanelli, and E. C. degli Uberti. Cyclooxygenase-2 inhibitors reverse chemoresistance phenotype in medullary thyroid carcinoma by a permeability glycoprotein-mediated mechanism. J. Clin. Endocrinol. Metab. 90:5754–5760 (2005). CrossRef
- A. S. Kalgutkar, A. B. Marnett, B. C. Crews, R. P. Remmel, and L. J. Marnett. Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. J. Med. Chem. 43:2860–2870 (2000). CrossRef
- T. Mosmann. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods. 65:55–63 (1983). CrossRef
- M. Thamotharan, S. Z. Bawani, X. Zhou, and S. A. Adibi. Hormonal regulation of oligopeptide transporter pept-1 in a human intestinal cell line. Am. J. Physiol. 276:C821–C826 (1999).
- S. Siissalo, L. Laitinen, M. Koljonen, K. S. Vellonen, H. Kortejarvi, A. Urtti, J. Hirvonen, and A. M. Kaukonen. Effect of cell differentiation and passage number on the expression of efflux proteins in wild type and vinblastine-induced Caco-2 cell lines. Eur. J. Pharm. Biopharm. 67:548–54 (2007). CrossRef
- A. Pfrunder, H. Gutmann, C. Beglinger, and J. Drewe. Gene expression of CYP3A4, ABC-transporters (MDR1 and MRP1-MRP5) and hPXR in three different human colon carcinoma cell lines. J. Pharm. Pharmacol. 55:59–66 (2003). CrossRef
- A. Geick, M. Eichelbaum, and O. Burk. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 276:14581–14587 (2001). CrossRef
- D. Ratnasinghe, P. J. Daschner, M. R. Anver, B. H. Kasprzak, P. R. Taylor, G. C. Yeh, and J. A. Tangrea. Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; is chemoprevention against multidrug resistance possible? Anticancer Res. 21:2141–2147 (2001).
- D. Kessel, W. T. Beck, D. Kukuruga, and V. Schulz. Characterization of multidrug resistance by fluorescent dyes. Cancer Res. 51:4665–4670 (1991).
- M. Fontaine, W. F. Elmquist, and D. W. Miller. Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayers. Life Sci. 59:1521–1531 (1996). CrossRef
- Y. Honjo, C. A. Hrycyna, Q. W. Yan, W. Y. Medina-Perez, R. W. Robey, A. van de Laar, T. Litman, M. Dean, and S. E. Bates. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res. 61:6635–6639 (2001).
- J. D. Allen, S. C. Jackson, and A. H. Schinkel. A mutation hot spot in the Bcrp1 (Abcg2) multidrug transporter in mouse cell lines selected for Doxorubicin resistance. Cancer Res. 62:2294–2299 (2002).
- O. Alqawi, S. Bates, and E. Georges. Arginine482 to threonine mutation in the breast cancer resistance protein ABCG2 inhibits rhodamine 123 transport while increasing binding. Biochem. J. 382:711–716 (2004). CrossRef
- R. W. Robey, Y. Honjo, A. van de Laar, K. Miyake, J. T. Regis, T. Litman, and S. E. Bates. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochim. Biophys. Acta. 1512:171–182 (2001). CrossRef
- K. E. Pedersen, A. Dorph-Pedersen, S. Hvidt, N. A. Klitgaard, and K. K. Pedersen. The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. Eur. J. Clin. Pharmacol. 22:123–127 (1982). CrossRef
- U. Puhlmann, C. Ziemann, G. Ruedell, H. Vorwerk, D. Schaefer, C. Langebrake, P. Schuermann, U. Creutzig, and D. Reinhardt. Impact of the cyclooxygenase system on doxorubicin-induced functional multidrug resistance 1 overexpression and doxorubicin sensitivity in acute myeloid leukemic HL-60 cells. J. Pharmacol. Exp. Ther. 312:346–354 (2005). CrossRef
- I. Tegeder, J. Pfeilschifter, and G. Geisslinger. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J. 15:2057–2072 (2001). CrossRef
- M. Bentires-Alj, V. Barbu, M. Fillet, A. Chariot, B. Relic, N. Jacobs, J. Gielen, M. P. Merville, and V. Bours. NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene. 22:90–97 (2003). CrossRef
- M. L. Smith, G. Hawcroft, and M. A. Hull. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur. J. Cancer. 36:664–74 (2000). CrossRef
- M. Goto, S. Masuda, H. Saito, and K. Inui. Decreased expression of P-glycoprotein during differentiation in the human intestinal cell line Caco-2. Biochem. Pharmacol. 66:163–170 (2003). CrossRef
- Cyclooxygenase Inhibitors Down Regulate P-glycoprotein in Human Colorectal Caco-2 Cell Line
Volume 25, Issue 9 , pp 1991-2001
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- COX-2 inhibitor
- Industry Sectors
- Author 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
- 2. IFR 141, Université Paris-sud XI, Châtenay-Malabry, 92296, France
- 3. Hôpital Pitié Salpetrière, Service de Pharmacie, Assistance Publique-Hopitaux de Paris, Paris, 75013, France