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Cellular and Molecular Life Sciences

, Volume 67, Issue 5, pp 797–806 | Cite as

Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations

  • Svenja D. Steinbrink
  • Carlo Pergola
  • Ulrike Bühring
  • Sven George
  • Julia Metzner
  • Astrid S. Fischer
  • Ann-Kathrin Häfner
  • Joanna M. Wisniewska
  • Gerd Geisslinger
  • Oliver Werz
  • Dieter Steinhilber
  • Thorsten J. MaierEmail author
Research Article

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.

Keywords

Cyclooxygenase Leukotrienes Leukocytes NSAIDs Off-target effect 

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

Notes

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.

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Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  • Svenja D. Steinbrink
    • 1
  • Carlo Pergola
    • 3
  • Ulrike Bühring
    • 3
  • Sven George
    • 1
  • Julia Metzner
    • 1
  • Astrid S. Fischer
    • 1
  • Ann-Kathrin Häfner
    • 1
  • Joanna M. Wisniewska
    • 1
  • Gerd Geisslinger
    • 2
  • Oliver Werz
    • 3
  • Dieter Steinhilber
    • 1
  • Thorsten J. Maier
    • 1
    Email author
  1. 1.Institute of Pharmaceutical Chemistry/ZAFESGoethe-UniversityFrankfurt/MainGermany
  2. 2.Pharmazentrum frankfurt/ZAFES, Institute of Clinical PharmacologyGoethe-UniversityFrankfurt/MainGermany
  3. 3.Department of Pharmaceutical Analytics, Pharmaceutical InstituteUniversity of TuebingenTuebingenGermany

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