BINDING OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS TO THE ALPHA -SUBUNIT OF THE TRIFUNCTIONAL PROTEIN OF LONG CHAIN FATTY ACID OXIDATION

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.