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

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

^*Institute of Pathology, University of Regensburg, D-93042 Regensburg, Germany; and ^¶Genetics and Molecular Biology Program and Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA 19107

Edited by Alfred G. Knudson Jr., Institute for Cancer Research, Philadelphia, PA, and approved July 31, 1998 (received for review May 7, 1998)

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.

Footnotes

↵ † J.R. and S.W. contributed equally to this work.
↵ ‡ To whom reprint requests should be addressed. e-mail: rfishel{at}hendrix.jci.tju.edu or josef.rueschoff{at}klinik.uni-regensburg.de.
↵ § Present address: Institute of Pathology, Klinikum Kassel, D-34225 Kassel, Germany.
This paper was submitted directly (Track II) to the Proceedings Office.
↵ ‖ Definition of microsatellite panel and MSI diagnostic definition was determined at a December 8–9, 1998 meeting sponsored by the NCI/ICG-HNPCC.
ABBREVIATIONS:

NSAID,

nonsteroidal anti-inflammatory drug;

MSI,

microsatellite instability;

MMR,

mismatch repair;

HNPCC,

hereditary nonpolyposis colorectal cancer;

MSH,

MutS homolog;

MLH,

MutL homolog;

PMS,

postmeiotic segregant;

PEP,

primer-extension preamplification;

APC,

adenomatous polyposis coli;

TUNEL,

terminal deoxynucleotidyltransferase-mediated UTP end labeling;

NCI,

National Cancer Institute;

ICG-HNPCC,

International Collaborative Group for HNPCC;

COX,

cyclooxygenase