Nonsteroidal anti-inflammatory drugs stimulate spermidine/spermine acetyltransferase and deplete polyamine content in colon cancer cells.
BACKGROUND
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colonic tumourigenesis and have an established usefulness in cancer prevention. Because polyamines are essential for neoplastic cell growth, the aim of this study was to evaluate the effect of NSAIDs (indomethacin, a nonselective COX-1 and COX-2 inhibitor) on polyamine metabolism in colon cancer cells.


METHODS
Both cell counting and thymidine incorporation into cellular DNA were used to assess colon cancer cell growth. Activities of polyamine-metabolising enzymes, polyamine content (HPLC) and ODC and c-myc protein expression (Western blot) were measured in colon cancer cells treated with indomethacin during logarithmic phase of proliferation.


RESULTS
Indomethacin impaired growth of human colon cancer cells (Caco-2 and HCT-116). As a result, ornithine decarboxylase activity and c-myc protein expression were decreased. Treatment with indomethacin induced intracellular oxidant formation in colon cancer cells significantly increased the spermidine/spermine-acetyltrasferase activity (SSAT) and enhanced polyamine acetylation and efflux from colon cancer cells. Impairment of cell growth by indomethacin could not be reversed by exogenous polyamines.


CONCLUSIONS
Taken together, our results suggest that NSAIDs affect polyamine metabolism in colon cancer cells by inducing SSAT activity, and that polyamine depletion in NSAID-treated colon cancer cells is mainly due to enhanced polyamine acetylation and irreversible depletion of intracellular polyamine pools.
Turchanowa
L
L
2nd Department of Medicine, Johann Wolfgang Goethe University, Theodor Stern Kai 7, D-60590 Frankfurt, Germany.
Dauletbaev
N
N
Milovic
V
V
Stein
J
J
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018938:Caco-2 Cells; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D009955:Ornithine Decarboxylase / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin; D007527:Isoenzymes; D008565:Membrane Proteins; D009955:Ornithine Decarboxylase; D016877:Oxidants; D011073:Polyamines; D011451:Prostaglandin-Endoperoxide Synthases; D016271:Proto-Oncogene Proteins c-myc; D000099228:Diamine N-Acetyltransferase; C496540:PTGS2 protein, human