title: Growth-suppressive effect of non-steroidal anti-inflammatory drugs on 11 colon-cancer cell lines and fluorescence differential display of genes whose expression is influenced by sulindac.
abstract: In addition to an anti-inflammatory effect, sulindac, one of the non-steroidal anti-inflammatory drugs (NSAIDs), has been shown to have a protective effect against the incidence and mortality of colorectal cancer. However, the molecular basis of its anti-proliferative function remains unclear. To investigate its molecular mechanism, we exposed 11 colon-cancer cell lines to NSAIDs such as aspirin, sulindac and the sulfide and sulfone metabolites of sulindac. Sensitivity to these drugs was dose- and time-dependent but varied from one cell line to another. Among the cell lines examined, sulindac showed a moderate anti-proliferative effect on HT-29 colon cancer cells and caused morphological changes, including an increase of cells with abnormal DNA content. We used the mRNA fluorescence differential display method with these cells to identify molecules that might contribute, through altered expression, to cellular changes in response to NSAIDs. Sixty-eight cDNA fragments were confirmed by RT-PCR to have significantly different expression levels following sulindac treatment. Thirty of these fragments proved to be novel cDNA sequences or identical to expressed sequence tags; the other 38 fragments were identical, or showed significant homology, to genes whose function was already known. Among the known genes differentially expressed in HT-29 cells after sulindac treatment were those encoding acetylglucosaminyltransferase, ferritin heavy chain, zinc finger protein 165, aldose reductase, carcinoembryonic antigen, aldoketoreductase, NF-kappaB-activating kinase, lysosome-associated protein, RhoE = 26 kDa GTPase homologue, NADH oxidoreductase, G/T mismatch bindingprotein, TM7SF3, ADP/ATP carrier-like protein and chromosome segregation protein. This variety among classes of proteins affected by sulindac in our experiments underscores the complexity of anti-proliferative mechanisms that may operate in colon-cancer cells treated with NSAIDs. Furthermore, identification of genes regulated by NSAIDs in colon-cancer cells should provide useful information to identify novel therapeutic targets for treatment and/or prevention of colon cancer.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Akashi
authors.forename: H J
authors.initials: HJ
authors.lastname: Han
authors.forename: M
authors.initials: M
authors.lastname: Iizaka
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018076:DNA, Complementary / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D013467:Sulindac; C025462:sulindac sulfide; C025463:sulindac sulfone; D001241:Aspirin