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

Abstract

NO-aspirin (NO-ASA), consisting of aspirin and a nitric oxide-releasing group, is safer than aspirin and effective in colon cancer prevention. Here, we examined the mechanism of action of NO-ASA by focusing primarily on its effects on the cell cycle. NO-ASA reduced the growth of several cell lines from colon, pancreas, skin, cervix and breast cancer much more potently than aspirin, with 24-h IC(50) values of 133-268 µM, while those of ASA were >1,000 µM. NO-ASA elevated the intracellular levels of reactive oxygen species, generating a state of oxidative stress. In all cell lines examined, NO-ASA induced cell cycle arrest in the G(2)/M phase transition accompanied by altered expression of G(2)/M transition-related proteins. In SW480 colon cancer cells NO-ASA modulated proteins controlling this transition. Thus, it markedly increased the levels of cyclin B1, decreased the expression of cyclin D1 and Cdc25C, and increased the Thr14/Tyr15-phosphorylation of Cdk1 while leaving unchanged its protein levels. These changes, including the G2/M arrest, were prevented by pretreating the cells with the anti-oxidant N-acetyl-cysteine, indicating that redox signaling is likely responsible for the cell cycle changes, a conclusion consistent with the known redox regulation of these proteins. Collectively, these results confirm the profound cytokinetic effect of NO-ASA and provide strong evidence that it regulates cell cycle transitions through its ability to induce oxidative stress, which activates redox signaling in the target cell.

• Authors: Li Gao, Jennie L Williams
• Journal: International journal of oncology (Int J Oncol) Vol. 41 Issue 1 Pg. 325-30 (Jul 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 22552812 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Nitric Oxide Donors
• Reactive Oxygen Species
• nitroxy-butyl-acetylsalicylic acid
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• Caspase 3
• Aspirin

Topics

• Antineoplastic Agents (pharmacology)
• Aspirin (analogs & derivatives, pharmacology)
• Caspase 3 (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Inhibitory Concentration 50
• Nitric Oxide Donors (pharmacology)
• Oxidative Stress (drug effects)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Reactive Oxygen Species (metabolism)