Cytotoxic amounts of cisplatin induce either checkpoint adaptation or apoptosis in a concentration‐dependent manner in cancer cells

Swift, Lucy; Golsteyn, Roy M.

doi:10.1111/boc.201500056

Cited by 27 publications

(26 citation statements)

References 45 publications

(69 reference statements)

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“…In accordance with these results, it was reported that cisplatin can induce either apoptosis or necrosis depending on the dose [20] and the metabolic and energy status of the cells [21].…”

Section: Untreated Hela Cells Had Intact Plasma Membranes and Numerousupporting

confidence: 74%

Anticancer activity of aqueous myrrh extract alone and in combination with cisplatin in HeLa cells

Ramadan¹,

Sait²,

Anfinan³

2017

Trop. J. Pharm Res

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Purpose: To study the impact of an aqueous myrrh extract on the proliferation of cervical cancer cells in vitro.Methods: First, 100 g of ground myrrh resin was boiled in 1000 mL of distilled water for 30 min. Different components of the decoction were identified using gas chromatography-mass spectrometry and high-performance liquid chromatography. The effects of high (20 µg/mL) and low (10 µg/mL) concentrations of cisplatin, serial concentrations of myrrh (20, 40, 60, and 80 µg/mL), and a combination of both were evaluated using cell proliferation assay, DNA fragmentation, and electron microscopy.

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“…In accordance with these results, it was reported that cisplatin can induce either apoptosis or necrosis depending on the dose [20] and the metabolic and energy status of the cells [21].…”

Section: Untreated Hela Cells Had Intact Plasma Membranes and Numerousupporting

confidence: 74%

Anticancer activity of aqueous myrrh extract alone and in combination with cisplatin in HeLa cells

Ramadan¹,

Sait²,

Anfinan³

2017

Trop. J. Pharm Res

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“…12 By contrast if the concentration of cisplatin applied to cells was at supra-pharmacological levels (100-300 mM), cells died within 48 h and do not undergo checkpoint adaptation. 10 …”

Section: Discussionmentioning

confidence: 99%

“…Although it was believed that cells would die by apoptosis when challenged by damaged DNA, cells have the possibility to engage another pathway known as checkpoint adaptation. 10 During checkpoint adaptation, cells enter mitosis despite having damaged DNA. 11,12 In these cells, the activity of Chk1 decreases, thus permitting the activation of Cdk1 followed by entry into mitosis damaged DNA.…”

Section: Introductionmentioning

confidence: 99%

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Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Lewis

Golsteyn

2016

Cell Cycle

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We have examined the relationship between checkpoint adaptation (mitosis with damaged DNA) and micronuclei. Micronuclei in cancer cells are linked to genomic change, and may induce chromothripsis (chromosome shattering). We measured the cytotoxicity of the cancer drug cisplatin in M059K (glioma fibroblasts, IC50 15 mM). Nearly 100% of M059K cells were positive for histone gH2AX staining after 48 h treatment with a cytotoxic concentration of cisplatin. The proportion of micronucleated cells, as confirmed by microscopy using DAPI and lamin A/C staining, increased from 24% to 48%, and the total micronuclei in surviving cells accumulated over time. Promoting entry into mitosis with a checkpoint inhibitor increased the number of micronuclei in cells whereas blocking checkpoint adaptation with a Cdk inhibitor reduced the number of micronuclei. Interestingly, some micronuclei underwent asynchronous DNA replication, relative to the main nuclei, as measured by deoxy-bromo-uracil (BrdU) staining. These micronuclei stained positive for histone gH2AX, which was linked to DNA replication, suggesting that micronuclei arise from checkpoint adaptation and that micronuclei may continue to damage DNA. By contrast the normal cell line WI-38 did not undergo checkpoint adaptation when treated with cisplatin and did not show changes in micronuclei number. These data reveal that the production of micronuclei by checkpoint adaptation is part of a process that contributes to genomic change.

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“…Importantly, checkpoint adaptation has been documented in both uni-and multicellular systems including budding yeast, Xenopus egg extracts, plant and cancer cells (Carballo et al, 2006;Kubara et al, 2012;Sandell and Zakian, 1993;Swift and Golsteyn, 2016;Syljuasen et al, 2006;Toczyski et al, 1997;Yoo et al, 2004). One striking similarity in the process of checkpoint adaptation across all organisms is the critical contribution of PLK1 (Liang et al, 2014) and its homologues such as budding yeast Cdc5 (Syljuasen et al, 2006;Toczyski et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents

Bender¹,

Vydzhak²,

Klermund³

et al. 2018

Preprint

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Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ repair-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibition, either pharmacologically, or genetically, drastically reduces the occurrence of resistant cells. Additionally, the aneuploid phenotypes of the resistant cells can be specifically targeted to induce cytotoxicity. We provide evidence that TORC1 inhibition with rapamycin, in combination with DNA damaging agents, can prevent both checkpoint adaptation and the continued growth of aneuploid resistant cells.

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Cytotoxic amounts of cisplatin induce either checkpoint adaptation or apoptosis in a concentration‐dependent manner in cancer cells

Abstract: Checkpoint adaptation might be a common biochemical pathway taken by human cancer cells in response to pharmacologically relevant, cytotoxic amounts of damaged DNA.

Cited by 27 publications

References 45 publications

Anticancer activity of aqueous myrrh extract alone and in combination with cisplatin in HeLa cells

Anticancer activity of aqueous myrrh extract alone and in combination with cisplatin in HeLa cells

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents

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