A novel mechanism for aspirin-mediated growth inhibition of human colon cancer cells.

Abstract

PURPOSE:

The molecular mechanisms by which aspirin and other nonsteroidal anti-inflammatory drugs exert chemopreventative effects in colon cancer are unclear and complex. Current investigations focus on the chemopreventive properties of nonsteroidal anti-inflammatory drugs, independent of their ability to inhibit cyclooxygenase (COX) activity, and presumably, identification of non-COX pathways will suggest new targets for clinical use. It was demonstrated recently that aspirin results in reduced microsatellite instability in colorectal cancer cells. We hypothesized that aspirin treatment might alter expression of DNA mismatch repair (MMR) proteins, representing another potential non-COX mechanism for its action.

EXPERIMENTAL DESIGN:

In this study, we have examined the effects of aspirin on the cellular growth rates, MMR protein levels, cell cycle analysis and apoptosis in MMR-deficient (HCT116) and MMR-proficient (HCT116+chr3 and SW480) human colon cancer cell lines.

RESULTS:

We found that treatment with aspirin inhibited the growth of these three cancer cell lines. In HCT116+chr3 cells, treatment with 1 mM of aspirin increased expression of the hMLH1 and hPMS2 proteins by 2.5-fold and 2-fold, respectively, and increased expression of the hMSH2 and hMSH6 proteins by 2-3-fold. For SW480 cells, treatment with 1 and 5 mM of aspirin increased expression of the hMLH1 and hPMS2 proteins by 2-4-fold and 3-5-fold, respectively, and increased expression of the hMSH2 and hMSH6 proteins by 3-7-fold. For all three of the cell lines, treatment with 1 and 2.5 mM of aspirin induced apoptosis at 48 and 72 h. Aspirin induced G(0)/G(1) cell cycle arrest in HCT116 cells.

CONCLUSIONS:

We conclude that aspirin acts through COX-independent mechanisms by resulting in an increase in MMR protein expression and subsequent apoptosis, which might serve as an additional means of growth inhibition in aspirin-treated human colon cancer cells.

• Authors: Ajay Goel, Dong Kyung Chang, Luigi Ricciardiello, Christoph Gasche, C Richard Boland
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 1 Pg. 383-90 (Jan 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12538492 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Coloring Agents
• DNA-Binding Proteins
• MSH3 protein, human
• MutS Homolog 3 Protein
• Tetrazolium Salts
• Thiazoles
• thiazolyl blue
• Aspirin

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis
• Aspirin (pharmacology)
• Blotting, Western
• Cell Cycle
• Cell Division (drug effects)
• Colonic Neoplasms (drug therapy)
• Coloring Agents (pharmacology)
• DNA-Binding Proteins (metabolism)
• Dose-Response Relationship, Drug
• G1 Phase
• Humans
• MutS Homolog 3 Protein
• Resting Phase, Cell Cycle
• Reverse Transcriptase Polymerase Chain Reaction
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)
• Time Factors
• Tumor Cells, Cultured