Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

Delphine Lissa, Laura Senovilla, Santiago Rello-Varona, Ilio Vitale, Mickaël Michaud, Federico Pietrocola, Alice Boilève, Florine Obrist, Chloé Bordenave, Pauline Garcia, Judith Michels, Mohamed Jemaà, Oliver Kepp, Maria Castedo, Guido Kroemer

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    62 Citations (Scopus)

    Résumé

    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 ApcMin/+ 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.

    langue originaleAnglais
    Pages (de - à)3020-3025
    Nombre de pages6
    journalProceedings of the National Academy of Sciences of the United States of America
    Volume111
    Numéro de publication8
    Les DOIs
    étatPublié - 25 févr. 2014

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