Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been shown to suppress transcription factor NF-κB, which controls the expression of genes such as cyclooxygenase (COX)-2 and cyclin D1, leading to inhibition of proliferation of tumor cells. There is no systematic study as to how these drugs differ in their ability to suppress NF-κB activation and NF-κB-regulated gene expression or cell proliferation. In the present study, we investigated the effect of almost a dozen different commonly used NSAIDs on tumor necrosis factor (TNF)-induced NF-κB activation and NF-κB-regulated gene products, and on cell proliferation. Dexamethasone, an anti-inflammatory steroid, was included for comparison with NSAIDs. As indicated by DNA binding, none of the drugs alone activated NF-κB. All compounds inhibited TNF-induced NF-κB activation, but with highly variable efficacy. The 50% inhibitory concentration required was 5.67, 3.49, 3.03, 1.25, 0.94, 0.60, 0.38, 0.084, 0.043, 0.027, 0.024, and 0.010 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. All drugs inhibited IκBα kinase and suppressed IκBα degradation and NF-κB-regulated reporter gene expression. They also suppressed NF-κB-regulated COX-2 and cyclin D1 protein expression in a dose-dependent manner. All compounds inhibited the proliferation of tumor cells, with 50% inhibitory concentrations of 6.09, 1.12, 0.65, 0.49, 1.01, 0.19, 0.36, 0.012, 0.016, 0.047, 0.013, and 0.008 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. Overall these results indicate that aspirin and ibuprofen are least potent, while resveratrol, curcumin, celecoxib, and tamoxifen are the most potent anti-inflammatory and antiproliferative agents of those we studied.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Abbreviations

NSAIDs:

nonsteroidal anti-inflammatory drugs

TNF:

tumor necrosis factor

IκB:

inhibitory subunit of NF-κB

IKK:

IκBα kinase

EMSA:

electrophoretic mobility shift assays

SEAP:

secretory alkaline phosphatase

COX:

cyclooxygenase

References

  • Aggarwal BB . (2003). Nat. Rev. Immunol., 3, 745–756.

  • Ashikawa K, Majumdar S, Banerjee S, Bharti AC, Shishodia S and Aggarwal BB . (2002). J. Immunol., 169, 6490–6497.

  • Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F and van Stolk RU . (2003). N. Engl. J. Med., 348, 891–899.

  • Bharti AC and Aggarwal BB . (2002). Biochem. Pharmacol., 64, 883–888.

  • Bharti AC, Takada Y, Shishodia S and Aggarwal BB . (2004). J. Biol. Chem., 279, 6065–6076.

  • Botting JH . (1999). Drugs Today (Barc.), 35, 225–235.

  • Bryant CE, Farnfield BA and Janicke HJ . (2003). Am. J. Vet. Res., 64, 211–215.

  • Callejas NA, Casado M, Bosca L and Martin-Sanz P . (2002). Hepatology, 35, 341–348.

  • Chuang SE, Yeh PY, Lu YS, Lai GM, Liao CM, Gao M and Cheng AL . (2002). Biochem. Pharmacol., 63, 1709–1716.

  • Coussens LM and Werb Z . (2002). Nature, 420, 860–867.

  • Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C, Ferrandina G, Fattorossi A, Isola G, Benedetti Panici P and Mancuso S . (1999). Br. J. Cancer, 79, 257–263.

  • Fernandez de Arriba A, Cavalcanti F, Miralles A, Bayon Y, Alonso A, Merlos M, Garcia-Rafanell J and Forn J . (1999). Mol. Pharmacol., 55, 753–760.

  • Ghosh S and Karin M . (2002). Cell, 109 (Suppl), S81–S96.

  • Giercksky KE . (2001). Best Pract. Res. Clin. Gastroenterol., 15, 821–833.

  • Goel A, Chang DK, Ricciardiello L, Gasche C and Boland CR . (2003). Clin. Cancer Res., 9, 383–390.

  • Guttridge DC, Albanese C, Reuther JY, Pestell RG and Baldwin Jr AS . (1999). Mol. Cell. Biol., 19, 5785–5799.

  • Hass R, Brach M, Gunji H, Kharbanda S and Kufe D . (1992). Biochem. Pharmacol., 44, 1569–1576.

  • Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C and Strauss M . (1999). Mol. Cell. Biol., 19, 2690–2698.

  • Inoue H, Yokoyama C, Hara S, Tone Y and Tanabe T . (1995). J. Biol. Chem., 270, 24965–24971.

  • Jack DB . (1997). Lancet, 350, 437–439.

  • Jung M and Dritschilo A . (2001). Semin. Radiat. Oncol., 11, 346–351.

  • Kazmi SM, Plante RK, Visconti V, Taylor GR, Zhou L and Lau CY . (1995). J. Cell. Biochem., 57, 299–310.

  • Kisley LR, Barrett BS, Dwyer-Nield LD, Bauer AK, Thompson DC and Malkinson AM . (2002). Carcinogenesis, 23, 1653–1660.

  • Kopp E and Ghosh S . (1994). Science, 265, 956–959.

  • Lawrence T, Willoughby DA and Gilroy DW . (2002). Nat. Rev. Immunol., 2, 787–795.

  • Manna SK, Mukhopadhyay A and Aggarwal BB . (2000). J. Immunol., 164, 6509–6519.

  • Miller C, Zhang M, He Y, Zhao J, Pelletier JP, Martel-Pelletier J and Di Battista JA . (1998). J. Cell Biochem., 69, 392–413.

  • Moysich KB, Menezes RJ, Ronsani A, Swede H, Reid ME, Cummings KM, Falkner KL, Loewen GM and Bepler G . (2002). BMC Cancer, 2, 31.

  • Nasuhara Y, Adcock IM, Catley M, Barnes PJ and Newton R . (1999). J. Biol. Chem., 274, 19965–19972.

  • Niederberger E, Tegeder I, Vetter G, Schmidtko A, Schmidt H, Euchenhofer C, Brautigam L, Grosch S and Geisslinger G . (2001). FASEB J., 15, 1622–1624.

  • O'Neill EA . (1998). Nature, 396, 15–17.

  • Roth GJ and Calverley DC . (1994). Blood, 83, 885–898.

  • Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G and Schilsky R . (2003). N. Engl. J. Med., 348, 883–890.

  • Scheuren N, Bang H, Munster T, Brune K and Pahl A . (1998). Br. J. Pharmacol., 123, 645–652.

  • Singh S and Aggarwal BB . (1995). J. Biol. Chem., 270, 24995–25000.

  • Stark LA, Din FV, Zwacka RM and Dunlop MG . (2001). FASEB J., 15, 1273–1275.

  • Takada Y and Aggarwal BB . (2003a). J. Immunol., 171, 3278–3286.

  • Takada Y and Aggarwal BB . (2003b). J. Biol. Chem., 278, 23390–23397.

  • Takada Y, Khuri FR and Aggarwal BB . (2004). J. Biol. Chem., 279, 26287–26299.

  • Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S and Aggarwal BB . (2003). J. Biol. Chem., 278, 24233–24241.

  • Tegeder I, Pfeilschifter J and Geisslinger G . (2001). FASEB J., 15, 2057–2072.

  • Vane JR . (1971). Nat. N. Biol., 231, 232–235.

  • Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA and Vane JR . (1999). Proc. Natl. Acad. Sci. USA, 96, 7563–7568.

  • Williams CS, Watson AJ, Sheng H, Helou R, Shao J and DuBois RN . (2000). Cancer Res., 60, 6045–6051.

  • Yamamoto K, Arakawa T, Ueda N and Yamamoto S . (1995). J. Biol. Chem., 270, 31315–31320.

  • Yamamoto Y, Yin MJ, Lin KM and Gaynor RB . (1999). J. Biol. Chem., 274, 27307–27314.

  • Yin MJ, Yamamoto Y and Gaynor RB . (1998). Nature, 396, 77–80.

Download references

Acknowledgements

We thank Mr Walter Pagel for carefully proof-reading the manuscript and providing valuable comments. Dr Aggarwal is a Ransom Horne Jr, Distinguished Professor of Cancer Research. This work was supported partially by the Clayton Foundation for Research (to BBA), Department of Defense US Army Breast Cancer Research Program Grant BC010610 (to BBA), a PO1 Grant (CA91844) from the National Institutes of Health on Lung Cancer Chemoprevention (to BBA), and a P50 Head and Neck SPORE Grant from the National Institutes of Health (to BBA).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bharat B Aggarwal.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Takada, Y., Bhardwaj, A., Potdar, P. et al. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 23, 9247–9258 (2004). https://doi.org/10.1038/sj.onc.1208169

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208169

Keywords

  • NSAID
  • NF-κB
  • IκBα
  • COX-2
  • cyclin D1
  • proliferation

This article is cited by

Search

Quick links