Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells

Haider Raza, Annie John, Sheela Benedict

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

Abstract

It is widely accepted that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, reduce the risk of cancer. The anti-cancer and anti-inflammatory effects of NSAIDs are associated with the inhibition of prostaglandin synthesis and cyclooxygenase-2 activity. Several other mechanisms which contribute to the anti-cancer effect of these drugs in different cancer models both in vivo and in vitro are also presumed to be involved. The precise molecular mechanism, however, is still not clear. We investigated, therefore, the effects of acetylsalicylic acid (ASA, aspirin) on multiple cellular and functional targets, including mitochondrial bioenergetics, using human hepatoma HepG2 cancer cells in culture. Our results demonstrate that ASA induced G0/G1 cell cycle arrest and apoptosis in HepG2 cells. ASA increased the production of reactive oxygen species, reduced the cellular glutathione (GSH) pool and inhibited the activities of the mitochondrial respiratory enzyme complexes, NADH-ubiquinone oxidoreductase (complex I), cytochrome c oxidase (complex IV) and the mitochondrial matrix enzyme, aconitase. Apoptosis was triggered by alteration in mitochondrial permeability transition, inhibition of ATP synthesis, decreased expression of the anti-apoptotic protein Bcl-2, release of cytochrome c and activation of pro-apoptotic caspase-3 and the DNA repairing enzyme, poly (- ADP-ribose) polymerase (PARP). These findings strongly suggest that ASA-induced toxicity in human hepatoma HepG2 cells is mediated by increased metabolic and oxidative stress, accompanied by mitochondrial dysfunction which result in apoptosis.

Original languageEnglish
Pages (from-to)15-24
Number of pages10
JournalEuropean Journal of Pharmacology
Volume668
Issue number1-2
DOIs
Publication statusPublished - Oct 1 2011

Keywords

  • Acetylsalicylic acid
  • Apoptosis
  • HepG2 cells
  • Mitochondrial functions
  • Oxidative stress

ASJC Scopus subject areas

  • Pharmacology

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