PubMed · 11534520
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B Senanayake, R De Silva. 2001. Lunchtime headache.. https://doi.org/10.1136/jnnp.71.3.415
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The synthesis and biological evaluation of a new family of diterpenes, represented by structures 2 and 3, is presented. These compounds constitute isomeric analogues of acanthoic acid (1) and were examined as potent anti-inflammatory agents. Among them, methyl ester 12 exhibited a low non-specific cytotoxicity, inhibited TNF-alpha synthesis and displayed good specificity in suppressing cytokine expression.
Naproxen, sulindac and salicylate, three NSAIDs (non-steroidal anti-inflammatory drugs), were cytotoxic to human colorectal cancer cells in culture. Toxicity was accompanied by significant depletion of intracellular polyamine content. Inhibition of ornithine decarboxylase (the first enzyme of the polyamine biosynthetic pathway), induction of polyamine oxidase and spermidine/spermine N(1)-acetyltransferase (the enzymes responsible for polyamine catabolism) and induction of polyamine export all contributed to the decreased intracellular polyamine content. Morphological examination of the cells showed typical signs of apoptosis, and this was confirmed by DNA fragmentation and measurement of caspase-3-like activity. Re-addition of spermidine to the cells partially prevented apoptosis and recovered the cell number. Thus polyamines appear to be an integral part of the signalling pathway mediating NSAID toxicity in human colorectal cancer cells, and may therefore also be important in cancer chemoprevention in humans.
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