Polyamines reverse non-steroidal anti-inflammatory drug-induced toxicity in human colorectal cancer cells.
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.
Hughes
Alun
A
Department of Medicine, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Smith
Nicholas I
NI
Wallace
Heather M
HM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism; D007364:Intercalating Agents / Q000378:metabolism; D009288:Naproxen / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D011073:Polyamines / Q000378:metabolism / Q000494:pharmacology*; D011700:Putrescine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D012459:Salicylates / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D013095:Spermidine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D013096:Spermine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D013467:Sulindac / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005456:Fluorescent Dyes; D007211:Indoles; D007364:Intercalating Agents; D011073:Polyamines; D012459:Salicylates; D013467:Sulindac; D013096:Spermine; C007293:DAPI; D009288:Naproxen; D013095:Spermidine; D011700:Putrescine