HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection.

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known cancer preventives, which have been largely attributed to their antiproliferative and apoptosis-inducing activities. In this study, we show that microsatellite instability (MSI) in colorectal cancer cells deficient for a subset of the human mismatch repair (MMR) genes (hMLH1, hMSH2, and hMSH6), is markedly reduced during exposure to aspirin or sulindac [or Clinoril, which is chemically related to indomethacin (Indocin)]. This effect was reversible, time and concentration dependent, and appeared independent of proliferation rate and cyclooxygenase function. In contrast, the MSI phenotype of a hPMS2-deficient endometrial cancer cell line was unaffected by aspirin/sulindac. We show that the MSI reduction in the susceptible MMR-deficient cells was confined to nonapoptotic cells, whereas apoptotic cells remained unstable and were eliminated from the growing population. These results suggest that aspirin/sulindac induces a genetic selection for microsatellite stability in a subset of MMR-deficient cells and may provide an effective prophylactic therapy for hereditary nonpolyposis colorectal cancer kindreds where alteration of the hMSH2 and hMLH1 genes are associated with the majority of cancer susceptibility cases.
AuthorsJ Rüschoff, S Wallinger, W Dietmaier, T Bocker, G Brockhoff, F Hofstädter, R Fishel
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 95 Issue 19 Pg. 11301-6 (Sep 15 1998) ISSN: 0027-8424 [Print] United States
PMID9736731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Anti-Inflammatory Agents, Non-Steroidal
  • Carrier Proteins
  • DNA-Binding Proteins
  • Fungal Proteins
  • MLH1 protein, human
  • MSH6 protein, S cerevisiae
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Saccharomyces cerevisiae Proteins
  • Sulindac
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Aspirin
Topics
  • Adaptor Proteins, Signal Transducing
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
  • Apoptosis (genetics)
  • Aspirin (pharmacology)
  • Carrier Proteins
  • Chemoprevention
  • Clone Cells (metabolism)
  • Cloning, Molecular
  • Colorectal Neoplasms, Hereditary Nonpolyposis (therapy)
  • DNA Repair (genetics)
  • DNA-Binding Proteins
  • Fungal Proteins (genetics)
  • Humans
  • Microsatellite Repeats (genetics)
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Mutation (genetics)
  • Neoplasm Proteins (genetics)
  • Nuclear Proteins
  • Phenotype
  • Proto-Oncogene Proteins (genetics)
  • Saccharomyces cerevisiae Proteins
  • Sulindac
  • Time Factors
  • Tumor Cells, Cultured

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: