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.

Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells

“…1, D and G). Therefore, we examined the senescenceinducing effects of 500 mM of aspirin, which is a 10-to 20-fold lower dose than that (5-10 mM) reported to be deadly against CRC cells (Din et al, 2012;Lissa et al, 2014). Clinically, the regular use of aspirin (375 mg) has been associated with a 20% (statistically significant) reduction in the risk of CRC (Usman et al, 2015).…”

“…Improving our understanding of how NSAIDs influence cancer metabolism could provide substantial insights into the mechanisms by which these unique agents control CRC cell growth, potentially directing the development of better prevention and treatment strategies. To date, aspirin has been shown to reduce the development of CRC through the direct activation of AMPK (Din et al, 2012;Lissa et al, 2014).…”

Genomic Instability or One-Gene Theory for Tumor Progression: A Breast Cancer Study

“…In view of the results in this report, this will provide information on how far the tumor has progressed in terms of genomic instability and malignancy potential even before mutation of oncogenes. If we look ahead a decade, drugs like the health food product resveratrol, which is derived from red grapes and has been found to inhibit tetraploidization [54], and might be a first line treatment for patients with diploid tumors as a block against tetraploidization in growing metastatic cells. In a further step, we can imagine a prophylactic treatment of reservatrol for high-risk people with inherited cancer genes.…”

Genome management and mismanagement—cell-level opportunities and challenges of whole-genome duplication

“…Why this is and whether it arises as a direct or indirect consequence of WGD are unclear, but similar patterns are seen elsewhere: Inhibition of Aurora kinases in acute myeloid leukemia cells also induces polyploidy, again coupled with increased glycolysis (Liu et al 2011), and, in glioblastoma, polyploid cells similarly show increased glycolysis and are hypersensitive to glycolysis inhibitors relative to their diploid counterparts (Donovan et al 2014). Other metabolic effects may also be linked to WGD: Aspirin and resveratrol selectively target polyploid cells by activating AMP kinase, a core sensor of cellular energy whose hyperactivation tetraploid cells are more sensitive to than diploid cells, for unknown reasons (Lissa et al 2014). Whether similar metabolic shifts occur in endopolyploid cells in other systems will be interesting to explore.…”