title: Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention.
abstract: Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc(Min/+) mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), U848, F-94805 Villejuif, France.
authors: Delphine
authors: D
authors: Lissa
authors: Laura
authors: L
authors: Senovilla
authors: Santiago
authors: S
authors: Rello-Varona
authors: Ilio
authors: I
authors: Vitale
authors: Mickaël
authors: M
authors: Michaud
authors: Federico
authors: F
authors: Pietrocola
authors: Alice
authors: A
authors: Boilève
authors: Florine
authors: F
authors: Obrist
authors: Chloé
authors: C
authors: Bordenave
authors: Pauline
authors: P
authors: Garcia
authors: Judith
authors: J
authors: Michels
authors: Mohamed
authors: M
authors: Jemaà
authors: Oliver
authors: O
authors: Kepp
authors: Maria
authors: M
authors: Castedo
authors: Guido
authors: G
authors: Kroemer
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000517:prevention & control*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects*; D005434:Flow Cytometry; D007091:Image Processing, Computer-Assisted; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D057891:Tetraploidy
chemical_list: D013267:Stilbenes; D000077185:Resveratrol; D001241:Aspirin