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

Alun Hughes1, Nicholas I Smith, Heather M Wallace

  • 1Department of Medicine, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.

The Biochemical Journal
|June 10, 2003
PubMed

Insights

Non-steroidal anti-inflammatory drugs (NSAIDs) like naproxen induce colorectal cancer cell death by depleting polyamines. Restoring polyamine levels partially prevents this NSAID-induced apoptosis, suggesting a role in cancer chemoprevention.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation.
  • Colorectal cancer (CRC) remains a significant global health challenge.
  • The molecular mechanisms underlying NSAID effects on cancer cells are not fully understood.

Purpose of the Study:

  • To investigate the role of intracellular polyamines in NSAID-induced cytotoxicity in human colorectal cancer cells.
  • To elucidate the specific polyamine metabolic pathways involved in NSAID toxicity.
  • To explore the potential of polyamines in cancer chemoprevention strategies.

Main Methods:

  • Human colorectal cancer cells were treated with NSAIDs (naproxen, sulindac, salicylate).
  • Intracellular polyamine levels, polyamine metabolic enzyme activities (ornithine decarboxylase, polyamine oxidase, spermidine/spermine N(1)-acetyltransferase), and polyamine export were measured.
  • Apoptosis was assessed via morphological changes, DNA fragmentation, and caspase-3-like activity.
  • The effect of exogenous spermidine re-addition on NSAID-induced apoptosis was evaluated.

Main Results:

  • NSAIDs exhibited significant cytotoxicity towards human colorectal cancer cells in vitro.
  • Cytotoxicity correlated with a marked decrease in intracellular polyamine content.
  • NSAIDs modulated polyamine metabolism by inhibiting synthesis and inducing catabolism and export.
  • NSAID treatment induced apoptosis, confirmed by DNA fragmentation and caspase-3-like activity.
  • Supplementation with spermidine partially rescued cells from apoptosis and restored cell numbers.

Conclusions:

  • Polyamines are integral to the signaling pathway mediating NSAID toxicity in human colorectal cancer cells.
  • NSAID-induced apoptosis in CRC cells is significantly influenced by alterations in polyamine homeostasis.
  • Targeting polyamine metabolism could represent a novel strategy for colorectal cancer chemoprevention.

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