, 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



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.


celecoxib FTS Ras T cells 





extracellular signal regulated kinase


farnesylthiosalicylic acid


green fluorescent protein


intercellular adhesion molecule 1




leukocyte function associated antigen 1


non-steroidal anti-inflammatory drugs




Ras proximate 1


rat sarcoma viral oncogene


Ras binding domain


red fluorescent protein



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)


  1. 1.
    Burmester, G., A. Lanas, L. Biasucci, M. Hermann, S. Lohmander, I. Olivieri, et al. 2011. The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel. Annals of the Rheumatic Diseases 70: 818–822.PubMedCrossRefGoogle Scholar
  2. 2.
    Arber, N., C.J. Eagle, J. Spicak, I. Rácz, P. Dite, J. Hajer, et al. 2006. Celecoxib for the prevention of colorectal adenomatous polyps. The New England Journal of Medicine 355: 885–895.PubMedCrossRefGoogle Scholar
  3. 3.
    Mor, A., R. Haklai, O. Ben-Moshe, Y.A. Mekori, and Y. Kloog. 2011. Inhibition of contact sensitivity by farnesylthiosalicylic acid-amide, a potential Rap1 inhibitor. The Journal of Investigative Dermatology 131: 2040–2048.PubMedCrossRefGoogle Scholar
  4. 4.
    Aizman, E., A. Mor, J. Chapman, Y. Assaf, and Y. Kloog. 2010. The combined treatment of Copaxone and Salirasib attenuates experimental autoimmune encephalomyelitis (EAE) in mice. Journal of Neuroimmunology 229: 192–203.PubMedCrossRefGoogle Scholar
  5. 5.
    Mor, A., O. Ben-Moshe, Y.A. Mekori, and Y. Kloog. 2011. Inhibitory effect of farnesylthiosalicylic acid on mediators release by mast cells: preferential inhibition of prostaglandin D2 and tumor necrosis factor-α release. Inflammation 34: 314–318.PubMedCrossRefGoogle Scholar
  6. 6.
    Hoang, B., L. Zhu, Y. Shi, P. Frost, H. Yan, S. Sharma, et al. 2006. Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance. Blood 107: 4484–4490.PubMedCrossRefGoogle Scholar
  7. 7.
    Capodici, C., M.H. Pillinger, G. Han, M.R. Philips, and G. Weissmann. 1998. Integrin-dependent homotypic adhesion of neutrophils. Arachidonic acid activates Raf-1/Mek/Erk via a 5-lipoxygenase-dependent pathway. The Journal of Clinical Investigation 102: 165–175.PubMedCrossRefGoogle Scholar
  8. 8.
    Mor, A., M.L. Dustin, and M.R. Philips. 2007. Small GTPases and LFA-1 reciprocally modulate adhesion and signaling. Immunological Reviews 218: 114–125.PubMedCrossRefGoogle Scholar
  9. 9.
    Mor, A., G. Campi, G. Du, Y. Zheng, D.A. Foster, M.L. Dustin, et al. 2007. The lymphocyte function-associated antigen-1 receptor costimulates plasma membrane Ras via phospholipase D2. Nature Cell Biology 9: 713–719.PubMedCrossRefGoogle Scholar
  10. 10.
    Chou, T.C. 2010. Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Research 70: 440–446.PubMedCrossRefGoogle Scholar
  11. 11.
    Patel, M.I., K. Subbaramaiah, B. Du, M. Chang, P. Yang, R.A. Newman, et al. 2005. Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism. Clinical Cancer Research 11: 1999–2007.PubMedCrossRefGoogle Scholar
  12. 12.
    Du, J., B. Jiang, and J. Barnard. 2005. Differential regulation of cyclooxygenase-2 in nontransformed and ras-transformed intestinal epithelial cells. Neoplasia 7: 761–770.PubMedCrossRefGoogle Scholar
  13. 13.
    Repasky, G.A., Y. Zhou, S. Morita, and C.J. Der. 2007. Ras-mediated intestinal epithelial cell transformation requires cyclooxygenase-2-induced prostaglandin E2 signaling. Molecular Carcinogenesis 46: 958–970.PubMedCrossRefGoogle Scholar
  14. 14.
    Funahashi, H., M. Satake, D. Dawson, N.A. Huynh, H.A. Reber, O.J. Hines, et al. 2007. Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Research 67: 7068–7071.PubMedCrossRefGoogle Scholar
  15. 15.
    Pillinger, M.H., C. Capodici, P. Rosenthal, N. Kheterpal, S. Hanft, M.R. Philips, et al. 1998. Modes of action of aspirin-like drugs: salicylates inhibit erk activation and integrin-dependent neutrophil adhesion. Proceedings of the National Academy of Sciences of the United States of America 95: 14540–14545.PubMedCrossRefGoogle Scholar
  16. 16.
    Wang, D., F.G. Buchanan, H. Wang, S.K. Dey, and R.N. DuBois. 2005. Prostaglandin E2 enhances intestinal adenoma growth via activation of the Ras-mitogen-activated protein kinase cascade. Cancer Research 65: 1822–1829.PubMedCrossRefGoogle Scholar
  17. 17.
    Dajani, O.F., K. Meisdalen, T.K. Guren, M. Aasrum, I.H. Tveteraas, P. Lilleby, et al. 2008. Prostaglandin E2 upregulates EGF-stimulated signaling in mitogenic pathways involving Akt and ERK in hepatocytes. Journal of Cellular Physiology 214: 371–380.PubMedCrossRefGoogle Scholar
  18. 18.
    Grösch, S., I. Tegeder, E. Niederberger, L. Bräutigam, and G. Geisslinger. 2001. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. The FASEB Journal 15: 2742–2744.Google Scholar
  19. 19.
    Jendrossek, V., R. Handrick, and C. Belka. 2003. Celecoxib activates a novel mitochondrial apoptosis signaling pathway. The FASEB Journal 17: 1547–1549.Google Scholar
  20. 20.
    Brueggemann, L.I., A.R. Mackie, B.K. Mani, L.L. Cribbs, and K.L. Byron. 2009. Differential effects of selective cyclooxygenase-2 inhibitors on vascular smooth muscle ion channels may account for differences in cardiovascular risk profiles. Molecular Pharmacology 76: 1053–1061.PubMedCrossRefGoogle Scholar
  21. 21.
    Iñiguez, M.A., C. Punzón, and M. Fresno. 1999. Induction of cyclooxygenase-2 on activated T lymphocytes: regulation of T cell activation by cyclooxygenase-2 inhibitors. Journal of Immunology 163: 111–119.Google Scholar
  22. 22.
    Iñiguez, M.A., C. Punzón, C. Cacheiro-Llaguno, M.D. Díaz-Muñoz, J. Duque, R. Cuberes, et al. 2010. Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors. International Immunopharmacology 10: 1295–1304.PubMedCrossRefGoogle Scholar

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

Personalised recommendations