Polyamines reverse non-steroidal anti-inflammatory drug-induced toxicity in human colorectal cancer cells

Alun Hughes, Natalie Smith, Heather Mann Wallace

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Naproxen, sulindac and salicylate, three NSAIDs (nonsteroidal 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'-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 apophosis, 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.

Original languageEnglish
Pages (from-to)481-488
Number of pages7
JournalBiochemical Journal
Volume374
Issue number2
DOIs
Publication statusPublished - 2003

Keywords

  • apoptosis
  • colorectal cancer
  • chemoprevention
  • non-steroidal anti-inflammatory drug
  • polyamine
  • spermidine
  • spermine
  • ORNITHINE DECARBOXYLASE ACTIVITY
  • MITOCHONDRIAL PERMEABILITY TRANSITION
  • HUMAN COLON
  • SULINDAC SULFIDE
  • SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE
  • ALPHA-DIFLUOROMETHYLORNITHINE
  • PROSTAGLANDIN E-2
  • APOPTOSIS
  • LINES
  • TRANSFORMATION

Cite this

Polyamines reverse non-steroidal anti-inflammatory drug-induced toxicity in human colorectal cancer cells. / Hughes, Alun; Smith, Natalie; Wallace, Heather Mann.

In: Biochemical Journal, Vol. 374, No. 2, 2003, p. 481-488.

Research output: Contribution to journalArticle

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abstract = "Naproxen, sulindac and salicylate, three NSAIDs (nonsteroidal 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'-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 apophosis, 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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AU - Smith, Natalie

AU - Wallace, Heather Mann

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N2 - Naproxen, sulindac and salicylate, three NSAIDs (nonsteroidal 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'-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 apophosis, 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.

AB - Naproxen, sulindac and salicylate, three NSAIDs (nonsteroidal 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'-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 apophosis, 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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KW - PROSTAGLANDIN E-2

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