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Nitric oxide-donating aspirin induces G2/M phase cell cycle arrest in human cancer cells by regulating

Li Gao1, Jennie L Williams

  • 1Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794-8175, USA.

International Journal of Oncology
|May 4, 2012
PubMed

Insights

NO-aspirin (NO-ASA) is a safer, more potent colon cancer preventative than aspirin. It halts cancer cell growth by inducing oxidative stress and G2/M cell cycle arrest through redox signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Aspirin (ASA) is effective in cancer prevention, but has gastrointestinal side effects.
  • Nitric oxide-releasing aspirin (NO-ASA) offers a potentially safer alternative.
  • Understanding NO-ASA's mechanism of action is crucial for its therapeutic application.

Purpose of the Study:

  • To investigate the mechanism by which NO-ASA inhibits cancer cell growth, focusing on its effects on the cell cycle.
  • To compare the potency of NO-ASA and aspirin in inhibiting the growth of various cancer cell lines.

Main Methods:

  • NO-ASA and aspirin efficacy were assessed by measuring 24-h IC(50) values across multiple cancer cell lines (colon, pancreas, skin, cervix, breast).
  • Intracellular reactive oxygen species (ROS) levels were measured to assess oxidative stress induction.
  • Cell cycle progression and the expression of key cell cycle regulatory proteins (cyclin B1, cyclin D1, Cdc25C, Cdk1) were analyzed in NO-ASA-treated cells.
  • The role of oxidative stress was confirmed using the antioxidant N-acetyl-cysteine (NAC).

Main Results:

  • NO-ASA demonstrated significantly greater potency than aspirin in inhibiting cancer cell growth (IC(50) 133-268 µM vs. >1,000 µM).
  • NO-ASA elevated intracellular ROS levels, inducing oxidative stress.
  • NO-ASA caused cell cycle arrest at the G(2)/M phase transition in all tested cell lines.
  • Specific modulation of G(2)/M proteins was observed in SW480 colon cancer cells, including increased cyclin B1, decreased cyclin D1 and Cdc25C, and increased Cdk1 phosphorylation.
  • The observed effects, including G(2)/M arrest, were reversed by NAC treatment, confirming the involvement of oxidative stress and redox signaling.

Conclusions:

  • NO-ASA exhibits a potent cytokinetic effect, significantly inhibiting cancer cell growth more effectively than aspirin.
  • NO-ASA's mechanism involves the induction of oxidative stress, which subsequently activates redox signaling pathways.
  • These redox signaling events lead to cell cycle arrest at the G(2)/M phase by modulating key regulatory proteins, providing a clear mechanism for its anti-cancer activity.

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