A Novel Approach to Safer Glucocorticoid Receptor–Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition

Abstract NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-κB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.

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A novel approach for organelle-specific DNA damage targeting reveals different susceptibility of mitochondrial DNA to the anticancer drugs camptothecin and topotecan

Nucleic Acids Research ◽

10.1093/nar/gkn1087 ◽

2009 ◽

Vol 37 (4) ◽

pp. e26-e26 ◽

Cited By ~ 17

Author(s):

M. C. Díaz de la Loza ◽

R. E. Wellinger

Keyword(s):

Dna Damage ◽

Mitochondrial Dna ◽

Anticancer Drugs ◽

Novel Approach

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Stress hormones promote DNA damage in human oral keratinocytes

Scientific Reports ◽

10.1038/s41598-021-99224-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Vitor Bonetti Valente ◽

Diovana de Melo Cardoso ◽

Giseli Mitsuy Kayahara ◽

Giovana Barros Nunes ◽

Kellen Cristine Tjioe ◽

...

Keyword(s):

Dna Damage ◽

Glucocorticoid Receptor ◽

Receptor Antagonist ◽

Stress Hormones ◽

Oral Keratinocytes ◽

Dna Breaks ◽

Genotoxic Effects ◽

Beta Adrenergic ◽

Pre Treatment ◽

Antagonist Ru486

AbstractChronic stress increases the systemic levels of stress hormones norepinephrine and cortisol. As well as tobacco-specific carcinogen NNK (4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone), they can induce expressive DNA damage contributing to the cancer development. However, it is unknown whether stress hormones have genotoxic effects in oral keratinocytes. This study investigated the effects of stress hormones on DNA damage in a human oral keratinocyte cell line (NOK-SI). NOK-SI cells stimulated with norepinephrine or cortisol showed higher DNA damage compared to untreated cells. Norepinephrine-induced DNA damage was reversed by pre-treatment with beta-adrenergic blocker propranolol. Cells treated with NNK combined to norepinephrine displayed reduced levels of caspases 3 and 7. Cortisol also reduced the activity of pro-apoptotic enzymes. NNK or norepinephrine promoted single-strand breaks and alkali-label side breaks in the DNA of NOK-SI cells. Pre-treatment of cells with propranolol abolished these effects. Carcinogen NNK in the presence or absence of cortisol also induced DNA damage of these cells. The genotoxic effects of cortisol alone and hormone combined with NNK were blocked partially and totally, respectively, by the glucocorticoid receptor antagonist RU486. DNA damage promoted by NNK or cortisol and carcinogen combined to the hormone led to intracellular γH2AX accumulation. The effects caused by NNK and cortisol were reversed by propranolol and glucocorticoid receptor antagonist RU486, respectively. Propranolol inhibited the oxidation of basis induced by NNK in the presence of DNA-formamidopyrimidine glycosylase. DNA breaks induced by norepinephrine in the presence or absence of NNK resulted in higher 8OHdG cellular levels. This effect was also induced through beta-adrenergic receptors. Together, these findings indicate that stress hormones induce DNA damage of oral keratinocytes and could contribute to oral carcinogenesis.

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Novel insights into the mode of action of 1,4-dioxane using a systems screening approach

10.1101/2020.12.27.424470 ◽

2020 ◽

Author(s):

Georgia Charkoftaki ◽

Jaya Prakash Golla ◽

Alvaro Santos-Neto ◽

David J. Orlicky ◽

Rolando Garcia-Milian ◽

...

Keyword(s):

Dna Damage ◽

Drinking Water ◽

Immunohistochemical Analysis ◽

The United States ◽

Environmental Chemicals ◽

Dna Double Strand Breaks ◽

Dna Damage And Repair ◽

Mechanisms Of Toxicity ◽

Novel Approach ◽

Histopathological Studies

Abstract1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

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Pseudopterosin Inhibits Proliferation and 3D Invasion in Triple Negative Breast Cancer by Agonizing Glucocorticoid Receptor Alpha

10.20944/preprints201807.0224.v2 ◽

2018 ◽

Author(s):

Julia Sperlich ◽

Nicole Teusch

Keyword(s):

Breast Cancer ◽

Glucocorticoid Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Mononuclear Cells ◽

Biological Activities ◽

Tumor Spheroids ◽

Peripheral Blood Mononuclear ◽

Surrounding Matrix ◽

Novel Approach

Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that anti-proliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a co-culture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to monoculture. Notably, pseudopterosin proved to block cytokine elevation, representing key players in tumor progression, in the co-culture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy.

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A Novel Approach to DNA Damage Assessments: Measurement of the Thymine Glycol Lesion

Radiation Research ◽

10.1667/rr3534.1 ◽

2006 ◽

Vol 165 (4) ◽

pp. 438-444 ◽

Cited By ~ 11

Author(s):

Douglas T. Bailey ◽

Han-Chun C. DeFedericis ◽

Kellee F. Greene ◽

Herbert Iijima ◽

Edwin E. Budzinski ◽

...

Keyword(s):

Dna Damage ◽

Thymine Glycol ◽

Novel Approach

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Impact of Replication Stress in Human Papillomavirus Pathogenesis

Journal of Virology ◽

10.1128/jvi.01012-17 ◽

2018 ◽

Vol 93 (2) ◽

Cited By ~ 6

Author(s):

Cary A. Moody

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Human Papillomavirus ◽

Genomic Instability ◽

Viral Persistence ◽

Replication Stress ◽

Cell Cycle Checkpoints ◽

Premalignant Lesions ◽

Associated Lesions ◽

Novel Approach

ABSTRACTThe inactivation of critical cell cycle checkpoints by the human papillomavirus (HPV) oncoprotein E7 results in replication stress (RS) that leads to genomic instability in premalignant lesions. Intriguingly, RS tolerance is achieved through several mechanisms, enabling HPV to exploit the cellular RS response for viral replication and to facilitate viral persistence in the presence of DNA damage. As such, inhibitors of the RS response pathway may provide a novel approach to target HPV-associated lesions and cancers.

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Identification of dose-dependent DNA damage and repair responses from subchronic exposure to 1,4-dioxane in mice using a systems analysis approach

Toxicological Sciences ◽

10.1093/toxsci/kfab030 ◽

2021 ◽

Author(s):

Georgia Charkoftaki ◽

Jaya Prakash Golla ◽

Alvaro Santos-Neto ◽

David J Orlicky ◽

Rolando Garcia-Milian ◽

...

Keyword(s):

Dna Damage ◽

Drinking Water ◽

Immunohistochemical Analysis ◽

The United States ◽

Environmental Chemicals ◽

Dna Double Strand Breaks ◽

Dna Damage And Repair ◽

Mechanisms Of Toxicity ◽

Novel Approach ◽

Histopathological Studies

Abstract 1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

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γ-H2AX Foci Persistence at Chromosome Break Suggests Slow and Faithful Repair Phases Restoring Chromosome Integrity

Cancers ◽

10.3390/cancers11091397 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1397 ◽

Cited By ~ 2

Author(s):

Michelle Ricoul ◽

Tamizh Selvan Gnana Sekaran ◽

Patricia Brochard ◽

Cecile Herate ◽

Laure Sabatier

Keyword(s):

Dna Damage ◽

Chromosome Rearrangement ◽

Chromosome Break ◽

Dna Double Strand Breaks ◽

Chromosome Fusion ◽

Post Irradiation ◽

Dna Lesion ◽

Novel Approach ◽

Chromosome Integrity ◽

Kinetics Of

Many toxic agents can cause DNA double strand breaks (DSBs), which are in most cases quickly repaired by the cellular machinery. Using ionising radiation, we explored the kinetics of DNA lesion signaling and structural chromosome aberration formation at the intra- and inter-chromosomal level. Using a novel approach, the classic Premature Chromosome Condensation (PCC) was combined with γ-H2AX immunofluorescence staining in order to unravel the kinetics of DNA damage signalisation and chromosome repair. We identified an early mechanism of DNA DSB joining that occurs within the first three hours post-irradiation, when dicentric chromosomes and chromosome exchanges are formed. The slower and significant decrease of ”deleted chromosomes” and 1 acentric telomere fragments observed until 24 h post-irradiation, leads to the conclusion that a second and error-free repair mechanism occurs. In parallel, we revealed remaining signalling of γ-H2AX foci at the site of chromosome fusion long after the chromosome rearrangement formation. Moreover there is important signalling of foci on the site of telomere and sub-telomere sequences suggesting either a different function of γ-H2AX signalling in these regions or an extreme sensibility of the telomere sequences to DNA damage that remains unrepaired 24 h post-irradiation. In conclusion, chromosome repair happens in two steps, including a last and hardly detectable one because of restoration of the chromosome integrity.

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