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 (original) (raw)

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been shown to suppress transcription factor NF-_κ_B, 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-_κ_B activation and NF-_κ_B-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-_κ_B activation and NF-_κ_B-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-κ_B. All compounds inhibited TNF-induced NF-κ_B 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 I_κ_B_α kinase and suppressed I_κ_B_α degradation and NF-_κ_B-regulated reporter gene expression. They also suppressed NF-_κ_B-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.

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Abbreviations

NSAIDs:

nonsteroidal anti-inflammatory drugs

TNF:

tumor necrosis factor

I_κ_B:

inhibitory subunit of NF-_κ_B

IKK:

I_κ_B_α_ kinase

EMSA:

electrophoretic mobility shift assays

SEAP:

secretory alkaline phosphatase

COX:

cyclooxygenase

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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).

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1. Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas M.D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, 77030, TX, USA
   Yasunari Takada, Anjana Bhardwaj, Pravin Potdar & Bharat B Aggarwal

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1. Yasunari Takada
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2. Anjana Bhardwaj
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3. Pravin Potdar
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4. Bharat B Aggarwal
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Correspondence toBharat B Aggarwal.

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Takada, Y., Bhardwaj, A., Potdar, P. et al. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-_κ_B 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

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• Received: 21 April 2004
• Revised: 01 September 2004
• Accepted: 01 September 2004
• Published: 18 October 2004
• Issue Date: 09 December 2004
• DOI: https://doi.org/10.1038/sj.onc.1208169

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