Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy

Johnson, Danielle P.; Chandrasekharan, Mahesh B.; Dutreix, Marie; Bhaskara, Srividya

doi:10.3390/cancers13030381

Cited by 3 publications

(2 citation statements)

References 123 publications

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“…In addition to its functional role in the nucleosome to ensure genomic stability, ( γ )H2A.X has a specialized cellular function by signaling and initializing DNA repair [ 47 , 62 , 63 ]. The H2A.X phosphorylation is considered one of the first reactions in the cellular DDR, particularly to DNA DSBs, which are among the DNA lesions with the most pronounced cytotoxicity [ 64 , 65 ].…”

Section: Histone γ H2axmentioning

confidence: 99%

H2A.X Phosphorylation in Oxidative Stress and Risk Assessment in Plasma Medicine

Schütz

Stope²,

Bekeschus

2021

Oxidative Medicine and Cellular Longevity

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At serine139-phosphorylated gamma histone H2A.X (γH2A.X) has been established over the decades as sensitive evidence of radiation-induced DNA damage, especially DNA double-strand breaks (DSBs) in radiation biology. Therefore, γH2A.X has been considered a suitable marker for biomedical applications and a general indicator of direct DNA damage with other therapeutic agents, such as cold physical plasma. Medical plasma technology generates a partially ionized gas releasing a plethora of reactive oxygen and nitrogen species (ROS) simultaneously that have been used for therapeutic purposes such as wound healing and cancer treatment. The quantification of γH2A.X as a surrogate parameter of direct DNA damage has often been used to assess genotoxicity in plasma-treated cells, whereas no sustainable mutagenic potential of the medical plasma treatment could be identified despite H2A.X phosphorylation. However, phosphorylated H2A.X occurs during apoptosis, which is associated with exposure to cold plasma and ROS. This review summarizes the current understanding of γH2A.X induction and function in oxidative stress in general and plasma medicine in particular. Due to the progress towards understanding the mechanisms of H2A.X phosphorylation in the absence of DSB and ROS, observations of γH2A.X in medical fields should be carefully interpreted.

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Section: Histone γ H2axmentioning

confidence: 99%

H2A.X Phosphorylation in Oxidative Stress and Risk Assessment in Plasma Medicine

Schütz

Stope²,

Bekeschus

2021

Oxidative Medicine and Cellular Longevity

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“…It found that olaparib improved rPFS and objective response rate in comparison to treatment with enzalutamide or abiraterone, although concluded that further studies are required to better define the genetic mutations that will sensitize a cancer to olaparib. For patients with PCa and at least one alteration in BRCA1, BRCA2 or ATM (a serine threonine kinase involved in the processing of DSBs and in HRR) ( 90 , 91 ), overall survival was significantly longer for patients that received olaparib ( 79 ). However, analysis from the TRITON2 study of PARP inhibition with rucaparib found that of the 49 patients with mCRPC identified to have ATM mutation, only 4.1% showed a significant decline in PSA following treatment ( 92 ).…”

Section: Immunotherapies and Dna Repair Targeted Therapies: Precision...mentioning

confidence: 99%

Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

Harris

Metzler²,

Lothion-Roy³

et al. 2022

Front. Endocrinol.

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Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.

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ERCC1 Overexpression Increases Radioresistance in Colorectal Cancer Cells

Huang

Cheng

et al. 2022

Cancers

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Preoperative concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced rectal cancer patients, but 20–30% do not benefit from the desired therapeutic effects. Previous reports indicate that high levels of ERCC1 reduce the effectiveness of cisplatin-based CCRT; however, it remains unclear as to whether ERCC1 overexpression increases radiation resistance. To clarify the correlation between ERCC1 levels and radiation (RT) resistance, we established two cell lines (HCT116-Tet-on and COLO205-Tet-on), induced them to overexpress ERCC1, detected cell survival following exposure to radiation, established HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models, and detected tumor volume following exposure to radiation. We found that ERCC1 overexpression increased radiation resistance. After regulating ERCC1 levels and radiation exposure to verify the correlation, we noted that increased radiation resistance was dependent on ERCC1 upregulation in both cell lines. For further verification, we exposed HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models to radiation and observed that ERCC1 overexpression increased colorectal cancer tumor radioresistance in both. Combined, our results suggest that ERCC1 overexpression may serve as a suitable CCRT prognostic marker for colorectal cancer patients.

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Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy

Cited by 3 publications

References 123 publications

H2A.X Phosphorylation in Oxidative Stress and Risk Assessment in Plasma Medicine

H2A.X Phosphorylation in Oxidative Stress and Risk Assessment in Plasma Medicine

Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

ERCC1 Overexpression Increases Radioresistance in Colorectal Cancer Cells

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