Skip to main content
SpringerLink
Log in

Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug’s chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC50 ≈ 8–10 μM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC50 = 18.7 μM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC50 of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AA:

Arachidonic acid

Ada:

Adenosine deaminase

COX:

Cyclooxygenase

cPLA2-alpha:

Cytosolic phospholipase A2-alpha

FLAP:

5-Lipoxygenase-activating protein

fMLP:

N-formyl-methionyl-leucyl-phenylalanine

5-HETE:

5(S)-hydroxy-8,11,14-cis-6-trans-eicosa-tetraenoic acid

12-HETE:

12(S)-hydroxy-5,8-cis-10-trans-14-cis-eicosatetraenoic acid

15-HETE:

15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid

12-HHT:

12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid

LC–MS/MS:

Liquid chromatography coupled with tandem mass spectrometry

5-LO:

5-Lipoxygenase

LPS:

Lipopolysaccharide

LT:

Leukotriene

NSAID:

Non-steroidal anti-inflammatory drug

PGE2 :

Prostaglandin E2

SA:

Sodium arsenite

SC:

Sodium chloride

SSi:

Sulindac sulfide

SSo:

Sulindac sulfone

Sul:

Sulindac

References

  1. Parente L, Perretti M (2003) Advances in the pathophysiology of constitutive and inducible cyclooxygenases: two enzymes in the spotlight. Biochem Pharmacol 65:153–159

    Article  PubMed  CAS  Google Scholar 

  2. Grosch S, Maier TJ, Schiffmann S, Geisslinger G (2006) Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 98:736–747

    Article  PubMed  CAS  Google Scholar 

  3. Haanen C (2001) Sulindac and its derivatives: a novel class of anticancer agents. Curr Opin Investig Drugs 2:677–683

    PubMed  CAS  Google Scholar 

  4. Davies NM, Watson MS (1997) Clinical pharmacokinetics of sulindac. A dynamic old drug. Clin Pharmacokinet 32:437–459

    Article  PubMed  CAS  Google Scholar 

  5. Williams CS, Goldman AP, Sheng H, Morrow JD, DuBois RN (1999) Sulindac sulfide, but not sulindac sulfone, inhibits colorectal cancer growth. Neoplasia 1:170–176

    Article  PubMed  CAS  Google Scholar 

  6. Goluboff ET (2001) Exisulind, a selective apoptotic antineoplastic drug. Expert Opin Investig Drugs 10:1875–1882

    Article  PubMed  CAS  Google Scholar 

  7. Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875

    Article  PubMed  CAS  Google Scholar 

  8. Werz O, Steinhilber D (2006) Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther 112:701–718

    Article  PubMed  CAS  Google Scholar 

  9. Werz O, Burkert E, Samuelsson B, Radmark O, Steinhilber D (2002) Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes. Blood 99:1044–1052

    Article  PubMed  CAS  Google Scholar 

  10. Fischer L, Szellas D, Radmark O, Steinhilber D, Werz O (2003) Phosphorylation- and stimulus-dependent inhibition of cellular 5-lipoxygenase activity by nonredox-type inhibitors. FASEB J 17:949–951

    Article  PubMed  CAS  Google Scholar 

  11. Brungs M, Radmark O, Samuelsson B, Steinhilber D (1995) Sequential induction of 5-lipoxygenase gene expression and activity in Mono Mac 6 cells by transforming growth factor beta and 1, 25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 92:107–111

    Article  PubMed  CAS  Google Scholar 

  12. Werz O, Steinhilber D (1996) Selenium-dependent peroxidases suppress 5-lipoxygenase activity in B-lymphocytes and immature myeloid cells. The presence of peroxidase-insensitive 5-lipoxygenase activity in differentiated myeloid cells. Eur J Biochem 242:90–97

    Article  PubMed  CAS  Google Scholar 

  13. Werz O, Klemm J, Samuelsson B, Radmark O (2001) Phorbol ester up-regulates capacities for nuclear translocation and phosphorylation of 5-lipoxygenase in Mono Mac 6 cells and human polymorphonuclear leukocytes. Blood 97:2487–2495

    Article  PubMed  CAS  Google Scholar 

  14. Maier TJ, Tausch L, Hoernig M, Coste O, Schmidt R, Angioni C, Metzner J, Groesch S, Pergola C, Steinhilber D, Werz O, Geisslinger G (2008) Celecoxib inhibits 5-lipoxygenase. Biochem Pharmacol 76:862–872

    Article  PubMed  CAS  Google Scholar 

  15. Albert D, Zundorf I, Dingermann T, Muller WE, Steinhilber D, Werz O (2002) Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol 64:1767–1775

    Article  PubMed  CAS  Google Scholar 

  16. Surette ME, Palmantier R, Gosselin J, Borgeat P (1993) Lipopolysaccharides prime whole human blood and isolated neutrophils for the increased synthesis of 5-lipoxygenase products by enhancing arachidonic acid availability: involvement of the CD14 antigen. J Exp Med 178:1347–1355

    Article  PubMed  CAS  Google Scholar 

  17. Siemoneit U, Pergola C, Jazzar B, Northoff H, Skarke C, Jauch J, Werz O (2009) On the interference of boswellic acids with 5-lipoxygenase: mechanistic studies in vitro and pharmacological relevance. Eur J Pharmacol 606:246–254

    Article  PubMed  CAS  Google Scholar 

  18. Rouzer CA, Ford-Hutchinson AW, Morton HE, Gillard JW (1990) MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J Biol Chem 265:1436–1442

    PubMed  CAS  Google Scholar 

  19. Feißt C, Pergola C, Rakonjac M, Rossi A, Koeberle A, Dodt G, Hoffmann M, Hoernig C, Fischer L, Steinhilber D, Franke L, Schneider G, Radmark O, Sautebin L, Werz O (2009) Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo. Cell Mol Life Sci 66:2759–2771

    Article  PubMed  CAS  Google Scholar 

  20. Fischer L, Hornig M, Pergola C, Meindl N, Franke L, Tanrikulu Y, Dodt G, Schneider G, Steinhilber D, Werz O (2007) The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5-lipoxygenase products. Br J Pharmacol 152:471–480

    Article  PubMed  CAS  Google Scholar 

  21. Brideau C, Chan C, Charleson S, Denis D, Evans JF, Ford-Hutchinson AW, Fortin R, Gillard JW, Guay J, Guevremont D et al (1992) Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)- indol-2-yl]-2, 2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol 70:799–807

    PubMed  CAS  Google Scholar 

  22. Werz O (2002) 5-lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy 1:23–44

    Article  PubMed  CAS  Google Scholar 

  23. Radmark O, Werz O, Steinhilber D, Samuelsson B (2007) 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sci 32:332–341

    Article  PubMed  CAS  Google Scholar 

  24. Costa D, Gomes A, Reis S, Lima JL, Fernandes E (2005) Hydrogen peroxide scavenging activity by non-steroidal anti-inflammatory drugs. Life Sci 76:2841–2848

    Article  PubMed  CAS  Google Scholar 

  25. Santos F, Teixeira L, Lucio M, Ferreira H, Gaspar D, Lima JL, Reis S (2008) Interactions of sulindac and its metabolites with phospholipid membranes: an explanation for the peroxidation protective effect of the bioactive metabolite. Free Radic Res 42:639–650

    Article  PubMed  CAS  Google Scholar 

  26. Egan RW, Gale PH (1985) Inhibition of mammalian 5-lipoxygenase by aromatic disulfides. J Biol Chem 260:11554–11559

    PubMed  CAS  Google Scholar 

  27. Riendeau D, Denis D, Choo LY, Nathaniel DJ (1989) Stimulation of 5-lipoxygenase activity under conditions which promote lipid peroxidation. Biochem J 263:565–572

    PubMed  CAS  Google Scholar 

  28. Piazza GA, Alberts DS, Hixson LJ, Paranka NS, Li H, Finn T, Bogert C, Guillen JM, Brendel K, Gross PH, Sperl G, Ritchie J, Burt RW, Ellsworth L, Ahnen DJ, Pamukcu R (1997) Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res 57:2909–2915

    PubMed  CAS  Google Scholar 

  29. Soh JW, Weinstein IB (2003) Role of COX-independent targets of NSAIDs and related compounds in cancer prevention and treatment. Prog Exp Tumor Res 37:261–285

    Article  PubMed  CAS  Google Scholar 

  30. Meade EA, Smith WL, DeWitt DL (1993) Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 268:6610–6614

    PubMed  CAS  Google Scholar 

  31. Oshima M, Murai N, Kargman S, Arguello M, Luk P, Kwong E, Taketo MM, Evans JF (2001) Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res 61:1733–1740

    PubMed  CAS  Google Scholar 

  32. Duggan DE, Hooke KF, Hwang SS (1980) Kinetics of the tissue distributions of sulindac and metabolites. Relevance to sites and rates of bioactivation. Drug Metab Dispos 8:241–246

    PubMed  CAS  Google Scholar 

  33. Huls G, Koornstra JJ, Kleibeuker JH (2003) Non-steroidal anti-inflammatory drugs and molecular carcinogenesis of colorectal carcinomas. Lancet 362:230–232

    Article  PubMed  CAS  Google Scholar 

  34. Melstrom LG, Bentrem DJ, Salabat MR, Kennedy TJ, Ding XZ, Strouch M, Rao SM, Witt RC, Ternent CA, Talamonti MS, Bell RH, Adrian TA (2008) Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model. Clin Cancer Res 14:6525–6530

    Article  PubMed  CAS  Google Scholar 

  35. Romano M, Claria J (2003) Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 17:1986–1995

    Article  PubMed  CAS  Google Scholar 

  36. Rainsford KD (1977) The comparative gastric ulcerogenic activities of non-steroid anti-inflammatory drugs. Agents Actions 7:573–577

    Article  PubMed  CAS  Google Scholar 

  37. Rainsford KD (1993) Leukotrienes in the pathogenesis of NSAID-induced gastric and intestinal mucosal damage. Agents Actions 39(Spec No):C24–C26

    Article  PubMed  CAS  Google Scholar 

  38. Cronstein BN, Terkeltaub R (2006) The inflammatory process of gout and its treatment. Arthritis Res Ther 8(Suppl 1):S3

    Article  PubMed  CAS  Google Scholar 

  39. Serhan CN, Lundberg U, Weissmann G, Samuelsson B (1984) Formation of leukotrienes and hydroxy acids by human neutrophils and platelets exposed to monosodium urate. Prostaglandins 27:563–581

    Article  PubMed  CAS  Google Scholar 

  40. Ford-Hutchinson AW, Gresser M, Young RN (1994) 5-Lipoxygenase. Annu Rev Biochem 63:383–417

    Article  PubMed  CAS  Google Scholar 

  41. Werz O, Steinhilber D (2005) Development of 5-lipoxygenase inhibitors—lessons from cellular enzyme regulation. Biochem Pharmacol 70:327–333

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by the “Landes Offensive zur Entwicklung Wissenschaftlich Ökonomischer Exzellenz” (LOEWE), Lipid Signaling Forschungszentrum Frankfurt (LiFF) and the German Excellence Cluster “Cardio-Pulmonary System” (ECCPS). The authors thank Dr. Wesely Mcginnstraub, California, USA, for the linguistic revision of the manuscript. The authors declare no conflicting financial interests. C.P. received a Carl Zeiss stipend.

Author information

Authors and Affiliations

  1. Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Max-von-Laue-Str. 9, 60438, Frankfurt/Main, Germany

    Svenja D. Steinbrink, Sven George, Julia Metzner, Astrid S. Fischer, Ann-Kathrin Häfner, Joanna M. Wisniewska, Dieter Steinhilber & Thorsten J. Maier

  2. Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt/Main, Germany

    Gerd Geisslinger

  3. Department of Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany

    Carlo Pergola, Ulrike Bühring & Oliver Werz

Authors
  1. Svenja D. Steinbrink
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlo Pergola
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ulrike Bühring
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sven George
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julia Metzner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Astrid S. Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ann-Kathrin Häfner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joanna M. Wisniewska
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gerd Geisslinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Oliver Werz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dieter Steinhilber
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Thorsten J. Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thorsten J. Maier.

Additional information

S. D. Steinbrink and C. Pergola contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steinbrink, S.D., Pergola, C., Bühring, U. et al. Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations. Cell. Mol. Life Sci. 67, 797–806 (2010). https://doi.org/10.1007/s00018-009-0206-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-009-0206-0

Keywords

Search

Navigation