Selective Resistance of Tetraploid Cancer Cells against DNA Damage‐Induced Apoptosis

Castedo, Maria; Coquelle, Arnaud; Vitale, Ilio; Vivet, Sonia; Mouhamad, Shahul; Viaud, Sophie; Zitvogel, Laurence; Kroemer, Guido

doi:10.1196/annals.1378.004

Cited by 60 publications

(58 citation statements)

References 43 publications

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“…Oxaliplatin and CDDP are chemically related agents that induce apoptosis through DNA damage as well as cytoplasmic effects (Wang and Lippard, 2005), and against which tumors often (but not always) exhibit cross-resistance (Castedo et al, 2006). In spite of their similarity, however, CDDP and OXP differ fundamentally in their capacity to elicit immunogenic cell death, as shown here.…”

Section: Discussionmentioning

confidence: 73%

Immunogenic death of colon cancer cells treated with oxaliplatin

et al. 2009

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Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNAmediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.

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Section: Discussionmentioning

confidence: 73%

Immunogenic death of colon cancer cells treated with oxaliplatin

et al. 2009

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“…Indeed, Docetaxel-induced polyploidisation has been proposed to underlie chemoresistance and disease relapse (Mittal et al 2017). Additionally, the Kroemer lab described selective resistance of tetraploid cancer cells against DNA damage-induced apoptosis (Castedo et al 2006). As described early in this review, aneuploidy, but not polyploidy, was found to cause post-slippage apoptosis (Ohashi et al 2015).…”

Section: Polyploidy Multinucleation and Chemoresistancementioning

confidence: 96%

Consequences of mitotic slippage for antimicrotubule drug therapy

Cheng

Crasta

2017

Endocrine-Related Cancer

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Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells 'slip' to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.

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“…One may speculate that these polyploid cells have acquired resistance to apoptosis. Indeed, some tetraploidy cells are more resistant to DNA-damaging agents, 27 providing selective survival advantage for p53 mutant cells. 28 Alternatively, a small number of cells may have escaped the effects of VX-680 and remained diploid throughout the drug treatment and recovery period.…”

Section: Discussionmentioning

confidence: 99%

Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53

et al. 2010

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Chemotherapeutics (e.g., aurora kinase inhibitors) designed to target proliferative cells are often nonspecific for tumor cells as normal cycling cells are also susceptible. Indeed, one of the major dose-limiting toxicities of aurora kinase inhibitors is a dangerous depletion of neutrophils in patients. In this study we proposed a strategy to selectively target p53 mutant cells while sparing normal ones. The strategy is based on the understanding that normal cells have an intact p53 pathway but not tumor cells carrying p53 mutations. Nongenotoxic activation of p53 using nutlin led to a reversible activation of G1 and G2 arrest in normal cells, which prevents them from entering mitosis, thus protecting them from the side effects of aurora kinase inhibition (VX-680), namely endoreduplication and apoptosis. Cells carrying mutant p53 are selectively killed by the nutlin/VX-680 combination, whereas p53 wild-type cells retain their proliferative capacity. The major implications drawn from these results are:(1) reversible nongenotoxic activation of p53 may be used as a strategy for the chemoprotection of normal tissues, and (2) aurora kinase inhibitors may have alleviated side effects when used in combination with nutlin-like inhibitors. We highlight the distinct roles of p53 and p73 in mediating the cellular responses to VX-680 and suggest that dual protection by p53 and p73 are needed to guard against endoreduplication and polyploidy.

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Selective Resistance of Tetraploid Cancer Cells against DNA Damage‐Induced Apoptosis

Cited by 60 publications

References 43 publications

Immunogenic death of colon cancer cells treated with oxaliplatin

Immunogenic death of colon cancer cells treated with oxaliplatin

Consequences of mitotic slippage for antimicrotubule drug therapy

Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53

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