Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs) reduce the growth of colorectal carcinoma cell lines in vitro. The mechanism appears to be independent of cyclooxygenases, and the long chain fatty acid pathway has been suggested as an alternative inhibitory target. We now report that all NSAIDs tested bound to the α-subunit of the trifunctional protein of the long chain fatty acid oxidation pathway, as assessed by competition with125I-[Nle15]-gastrin2,17 in a covalent cross-linking assay. Furthermore the NSAIDs diclofenac and ibuprofen inhibited the 3-hydroxyacyl-CoA dehydrogenase activity intrinsic to the α-subunit. The potencies of NSAIDs as inhibitors of human colon carcinoma cell proliferation correlated well with their affinities for the α-subunit. We conclude that inhibition of long chain fatty acid oxidation via binding of NSAIDs to the α-subunit of the trifunctional protein may contribute to the inhibitory effects of NSAIDs on colorectal carcinoma cell growth.
Footnotes
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Send reprint requests to: Dr. G. S. Baldwin, Department of Surgery, A & RMC, Austin Campus, Studley Rd., Heidelberg, Victoria 3084, Australia.
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↵1 This work was supported in part by Grants 920527 and 960182 from the National Health and Medical Research Council of Australia.
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↵2 Current address: Walter and Eliza Hall Institute, P.O. Royal Melbourne Hospital, Victoria, 3050, Australia.
- Abbreviations:
- GBP
- gastrin-binding protein
- IC50
- concentration required for 50% inhibition
- MTT
- (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- NSAIDs
- nonsteroidal antiinflammatory drugs
- TPα
- α-subunit of the trifunctional protein
- Received November 12, 1997.
- Accepted April 28, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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