Inflammation

, Volume 35, Issue 5, pp 1706–1714 | Cite as

Celecoxib Enhances the Anti-inflammatory Effects of Farnesylthiosalicylic Acid on T Cells Independent of Prostaglandin E2 Production

Article

Abstract

Celecoxib (Celebrex®), a non-steroidal anti-inflammatory drug and selective cyclooxygenase-2 inhibitor, is widely used to treat arthritis and other inflammatory disorders. Awareness of its anti-proliferative properties has prompted another indication for its use, in preventing colon polyps in high-risk populations. Farnesylthiosalicylic acid (FTS; Salirasib®), designed to inhibit oncogenic Ras and currently under evaluation in phase I/II and II clinical trials, was recently shown by our group to exert anti-inflammatory effects on both lymphocytes and mast cells. Here we examined whether celecoxib combined with FTS would enhance this anti-inflammatory activity. While each drug separately inhibited Ras activation in these cells, their combination yielded more marked inhibition as well as further inhibition of ERK phosphorylation, lymphocyte adhesion, and interleukin-2 secretion. The inhibitory effects, moreover, were independent of prostaglandin E2 secretion. These data point to the promising potential of combined treatment with celecoxib and FTS for inflammatory disorders involving lymphocytes.

KEY WORDS

celecoxib FTS Ras T cells 

ABBREVIATION

COX

cyclooxygenase

ERK

extracellular signal regulated kinase

FTS

farnesylthiosalicylic acid

GFP

green fluorescent protein

ICAM-1

intercellular adhesion molecule 1

IL

interleukin

LFA-1

leukocyte function associated antigen 1

NSAIDs

non-steroidal anti-inflammatory drugs

PG

prostaglandin

Rap1

Ras proximate 1

Ras

rat sarcoma viral oncogene

RBD

Ras binding domain

RFP

red fluorescent protein

Notes

ACKNOWLEDGMENTS

This work was supported in part by The Israel Science Foundation (grant no. 662/10 awarded to Y.K.) and by the Prajs–Drimmer Institute for the Development of Anti-degenerative Drugs (Y.K. and E.A.). Y. Kloog is the incumbent of the Jack H. Skirball Chair in Applied Neurobiology. We thank S.R. Smith for editorial assistance. We are grateful to Dr. Mark Philips (NYU) for indispensible support, both with reagents and knowledge.

Supplementary material

10753_2012_9488_MOESM1_ESM.pdf (443 kb)
Supplementary Fig. 1 Ras and Rap1 inhibition by FTS and celecoxib in primary splenocytes. Primary CD4+ T cells obtained from spleens of Balb/c mice and were pretreated overnight with FTS (50 μM) or celecoxib (50 μM) or their combination, stimulated with anti-CD3 and anti-CD28 antibodies (both at 5 μg/μl) for 10 min, and analyzed by GST-RBD-Raf-1 pull-down assay for GTP-loaded Ras (a) and by GST-RBD-RalGDS pull-down assay for GTP-loaded Rap1 (b). Results shown are average of three experiments (values are means ± SEM; n = 3). (PDF 443 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Medicine, Division of RheumatologyNew York University School of MedicineNew YorkUSA
  2. 2.Department of Neurobiology, George S. Wise Faculty of Life SciencesTel Aviv UniversityTel AvivIsrael

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