35 research outputs found
Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53.
The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed
Balancing repair and tolerance of DNA damage caused by alkylating agents
Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity
Effect of genetic and environment on the polar fraction metabolome of commercial Brassica napus seeds: a multisite study
International audienc
Is it enough to use the traditional approach based on average values for basketball physical performance analysis?
Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells
Introduction
Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response.
Methods
In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO) and human ovarian cancer cells using ATR inhibitors (NU6027). In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed.
Results
ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells.
Conclusions
Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cell
FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage
Colon Cancer-associated DNA Polymerase β Variant Induces Genomic Instability and Cellular Transformation
Quantifying the human diet in the crosstalk between nutrition and health by multi-targeted metabolomics of food and microbiota-derived metabolites
Background Metabolomics is a powerful tool for investigating the association between nutrition and health status. Although urine is commonly employed for studying the metabolism and transformation of food components, the use of blood samples could be preferable to gain new insights into the bioavailability of diet-derived compounds and their involvement in health. However, the chemical complexity of blood samples hinders the analysis of this biological fluid considerably, which makes the development of novel and comprehensive analytical methods mandatory. Methods In this work, we optimized a multi-targeted metabolomics platform for the quantitative and simultaneous analysis of 450 food-derived metabolites by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. To handle the chemical complexity of blood samples, three complementary extraction methods were assayed and compared in terms of recovery, sensitivity, precision and matrix effects with the aim of maximizing metabolomics coverage: protein precipitation, reversed solid-phase extraction, and hybrid protein precipitation with solid-phase extraction-mediated phospholipid removal. Results After careful optimization of the extraction conditions, protein precipitation enabled the most efficient and high-throughput extraction of the food metabolome in plasma, although solid-phase extraction-based protocols provided complementary performance for the analysis of specific polyphenol classes. The developed method yielded accurate recovery rates with negligible matrix effects, and good linearity, as well as high sensitivity and precision for most of the analyzed metabolites. Conclusions The multi-targeted metabolomics platform optimized in this work enables the simultaneous detection and quantitation of 450 dietary metabolites in short-run times using small volumes of biological sample, which facilitates its application to epidemiological studies