DNA damage and the balance between survival and death in cancer biology

Roos, Wynand P.; Thomas, Alex; Kaina, Bernd

doi:10.1038/nrc.2015.2

Cited by 939 publications

(779 citation statements)

References 192 publications

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“…An increase in γH2AX and phosphorylated-CHK2 expression was also observed for 2-treatment (20 µM for 72 h). DNA damage, when left unrepaired, can lead to apoptosis [55], therefore, the expression of proteins associated to apoptosis were monitored. HMLER-shEcad cells dosed with 3 (0.5 µM for 72 h) exhibited a clear increase in the level of cleaved caspase 3 and 7 compared to untreated control cells, indicative of caspase-dependent apoptosis ( Figure S13).…”

Section: Resultsmentioning

confidence: 99%

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

2017

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Cancer stem cells (CSCs) are thought to be responsible for cancer relapse. CSCs are a subtype of cancer cells with the ability to differentiate, self-renew, and form secondary or tertiary tumors. Current cancer treatments-including chemotherapy, radiation, and surgery-effectively remove bulk cancer cells but are unable to eliminate CSCs. Here, we present the synthesis, characterization, and anti-CSC properties of a cobalt(III)-cyclam complex bearing two tolfenamic acid moieties, 3. Notably, 3 displays sub-micromolar potency towards breast CSCs and bulk breast cancer cells. Detailed mechanistic studies show that 3 is taken up readily by breast CSCs, enters the nucleus, causes DNA damage, and induces caspase-dependent apoptosis. Furthermore, 3 inhibits cyclooxygenase-2 (COX-2) expression in CSCs. The mechanism of action of 3 is similar to that of a naproxen-appended cobalt(III)-cyclam complex, 1 recently reported by our group. The advantage of 3 over 1 is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose.

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Section: Resultsmentioning

confidence: 99%

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

2017

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“…Drugs can cause DNA damage either directly or indirectly: Some drugs (mostly chemotherapeutics) directly intercalate between or covalently bind to DNA [78]. Other drugs lead to ROS that can bind to DNA and cause DNA damage, thereby indirectly activating the DNA damage response pathway [33,[79][80][81][82]. When the DNA damage is not properly repaired, it can ultimately lead to cancer.…”

Section: Dna Damage Response Pathwaymentioning

confidence: 99%

“…In this stress pathway, some form of DNA damage is the 'controlled variable' that activates the system, and activation of the pathway will lead to DNA repair. Because different types of damage need a different type of repair response or cell fate, the DNA damage response pathway consists of multiple modules, each dealing with different types of DNA damage [82].…”

Section: Mechanismmentioning

confidence: 99%

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Kuijper

Yang

Water

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs. ARTICLE HISTORY

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“…The fate of the cell, survival or death, upon DNA damage is determined following DNA repair, cell-cycle checks and the expression of apoptotic proteins (4). In arrested cells, polymerases are inactivated to inhibit DNA replication and transcription and are reactivated once DNA repair is complete (5). In a non-repaired or checkpoint-bypassed cell, however, cell death, via mechanisms including apoptosis, necrosis or mitotic catastrophe, depends on the balance between pro-survival and pro-apoptotic factors (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…In arrested cells, polymerases are inactivated to inhibit DNA replication and transcription and are reactivated once DNA repair is complete (5). In a non-repaired or checkpoint-bypassed cell, however, cell death, via mechanisms including apoptosis, necrosis or mitotic catastrophe, depends on the balance between pro-survival and pro-apoptotic factors (5,6). Proteins that induce cell death via checkpoint mechanisms are known as tumor suppressors; however, overactive proliferative proteins known as oncogenes may induce cancer formation (7).…”

Section: Introductionmentioning

confidence: 99%

MED28 increases the colony‑forming ability of breast cancer cells by stabilizing the ZNF224 protein upon DNA damage

2017

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Abstract. The regulation of gene expression by transcription factors serves a critical function in cell proliferation. Zinc-finger protein 224 (ZNF224), a Krüppel-associated-box-containing zinc finger protein, is known to serve a crucial function in integrating the transcriptional co-factors that activate transcriptional regulation pathways in the cell. A previous study demonstrated that ZNF224 enhances cell proliferation by downregulating the expression of p21 and p53. The present study identified mediator complex subunit 28 (MED28) as a potential binding partner for ZNF224; this was confirmed by co-immunoprecipitation and a surface plasmon resonance assay. Additionally, the KRAB domain at the N-terminal of ZNF224 interacts with the MED domain of MED28. Bimolecular fluorescence complementation analysis revealed that ZNF224 associates with MED28 in the nucleus. In addition, ZNF224 was rapidly degraded upon treatment with the DNA-damaging agent camptothecin (CPT). Transient overexpression of MED28 inhibited the CPT-mediated degradation of ZNF224, resulting in increased colony formation by MCF-7 cells. The molecular mechanisms that underlie the biological outcomes of MED28 expression have not yet been fully elucidated. The present study provides molecular evidence for the function of ZNF224 and MED28 in the DNA-damage response.

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DNA damage and the balance between survival and death in cancer biology

Cited by 939 publications

References 192 publications

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

MED28 increases the colony‑forming ability of breast cancer cells by stabilizing the ZNF224 protein upon DNA damage

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