Faculty Opinions recommendation of The DNA damage-induced cell death response: a roadmap to kill cancer cells.

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

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Abstract 849: Autophagic cell death response to benzyl isothiocyanate exposure in human breast cancer cells is mediated by FoxO1

10.1158/1538-7445.am2011-849 ◽

2011 ◽

Author(s):

Dong Xiao ◽

Ajay Bommareddy ◽

Shivendra V. Singh

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Autophagic Cell Death ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Benzyl Isothiocyanate ◽

Cell Death Response

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Myrcene Exhibits Antitumor Activity Against Lung Cancer Cells by Inducing Oxidative Stress and Apoptosis Mechanisms

Natural Product Communications ◽

10.1177/1934578x20961189 ◽

2020 ◽

Vol 15 (9) ◽

pp. 1934578X2096118

Author(s):

Xudong Bai ◽

Jin Tang

Keyword(s):

Oxidative Stress ◽

Lung Cancer ◽

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Metabolic Activity ◽

Lung Cancer Cells ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

A549 Lung

Myrcene, a natural olefinic hydrocarbon, possesses anti-inflammatory, analgesic, antibiotic, and antimutagenic properties, but its anticancer effect has not yet been elucidated. Hence, the present study was framed to investigate the molecular mechanism by which myrcene mediates the anticancer activity of A549 lung adenocarcinoma cells. In vitro, A549 lung cancer cells were cultured either with or without myrcene, and the effects on cellular metabolic activity, levels of reactive oxygen species (ROS), mitochondrial integrity, deoxyribonucleic acid (DNA) damage, and activity of caspases were analyzed. The study demonstrated that compared with control cells, myrcene induces cell death in a dose-dependent manner while inducing ROS levels. Further experiments revealed that the metabolic activity of the A549 lung adenocarcinoma cells was diminished with increased DNA damage and altered cellular integrity. In addition, increased activity of caspase-3 was also evidenced with reduced mitochondrial membrane potential synthesis in the myrcene-treated cells, which demonstrate that lung cancer cells experience signs of toxicity during myrcene treatment through the activation of the apoptosis mechanism via mitochondria-mediated cell death signaling and induction of oxidative stress. The results provide the first report on the evidence of anticancer activity and the possibility of a new drug that could be used for the treatment of lung cancer.

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Uniform Widespread Nuclear Phosphorylation of Histone H2AX Is an Indicator of Lethal DNA Replication Stress

Cancers ◽

10.3390/cancers11030355 ◽

2019 ◽

Vol 11 (3) ◽

pp. 355 ◽

Cited By ~ 12

Author(s):

Eric Moeglin ◽

Dominique Desplancq ◽

Sascha Conic ◽

Mustapha Oulad-Abdelghani ◽

Audrey Stoessel ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Drug Efficacy ◽

Replication Stress ◽

Strand Break ◽

Histone H2ax ◽

C Terminus ◽

Dna Replication Stress ◽

Stressed Cells

Phosphorylated histone H2AX (γ-H2AX), a central player in the DNA damage response (DDR), serves as a biomarker of DNA double-strand break repair. Although DNA damage is generally visualized by the formation of γ-H2AX foci in injured nuclei, it is unclear whether the widespread uniform nuclear γ-H2AX (called pan-nuclear) pattern occurring upon intense replication stress (RS) is linked to DDR. Using a novel monoclonal antibody that binds exclusively to the phosphorylated C-terminus of H2AX, we demonstrate that H2AX phosphorylation is systematically pan-nuclear in cancer cells stressed with RS-inducing drugs just before they die. The pan-nuclear γ-H2AX pattern is abolished by inhibition of the DNA-PK kinase. Cell death induction of cancer cells treated with increasing combinations of replication and kinase (ATR and Chk1) inhibitory drugs was proportional to the appearance of pan-nuclear γ-H2AX pattern. Delivery of labeled anti-γ-H2AX Fabs in stressed cells demonstrated at a single cell level that pan-nuclear γ-H2AX formation precedes irreversible cell death. Moreover, we show that H2AX is not required for RS-induced cell death in HeLa cells. Thus, the nuclear-wide formation of γ-H2AX is an incident of RS-induced cell death and, thus, the pan nuclear H2AX pattern should be regarded as an indicator of lethal RS-inducing drug efficacy.

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