Journal
JOURNAL OF MOLECULAR MEDICINE-JMM
Volume 87, Issue 10, Pages 981-993Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00109-009-0506-8
Keywords
NSAIDs; Intracellular accumulation; Non-COX-2 targets; NOESY-NMR; Cyclooxygenase; Colon cancer
Funding
- Deutsche Forschungsgemeinschaft (DFG) Forschergruppe [FG 784/TP5, 757/1]
- Landes Offensive zur Entwicklung Wissenschaftlich Okonomischer Exzellenz (LOEWE) Lipid Signaling Forschungszentrum Frankfurt (LiFF)
- European Graduate School
- Marie Christine Held and Erika Hecker foundation
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Celecoxib is a selective cyclooxygenase-2-(COX-2)-inhibitor used to treat inflammation and pain and prevents colorectal cancer in patients at high doses by affecting several non-COX-2 proteins. However, celecoxib concentrations appropriate to inhibit proliferation or to induce apoptosis in cell culture (up to 100 A mu M) clearly exceed those in human plasma (up to 10 A mu M). Therefore, we speculated that celecoxib might accumulate in human cells, which may facilitate the drug's interaction with non-COX-2 proteins. Determination of intracellular celecoxib concentrations by liquid chromatography tandem mass spectrometry gave five- to tenfold higher levels as compared to other coxibs (etoricoxib, valdecoxib, lumiracoxib, and rofecoxib) in different tumor cell types, including human HCA-7 and HCT-116 colon carcinoma cells, BL-41 B lymphocytes, Mono Mac 6 monocytes, and in mouse NIH-3T3 non-tumor fibroblasts. This intracellular accumulation of celecoxib was due to an integration of the drug into cellular phospholipid membranes as demonstrated by nuclear Overhauser spectroscopy/nuclear magnetic resonance. Consequently, celecoxib disturbed the plasma membrane integrity of HCT-116 cells and displayed an increased COX-2-inhibitory potency in HCA-7 cells. The use of other coxibs demonstrated that intracellular accumulation is peculiar of celecoxib. Accumulation of celecoxib in human cells may provide a novel molecular basis for the ability of the drug to interact with non-COX-2 targets in vivo despite comparatively low plasma concentrations.
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