Ataxia-telangiectasia mutated (ATM) kinase orchestrates nuclear DNA damage responses but is proposed to be involved in other important and clinically relevant functions. Here, we provide evidence for what believe are 2 novel intertwined roles ATM: the regulation of ribonucleotide reductase (RR), rate-limiting enzyme de novo synthesis deoxyribonucleoside triphosphates, control mitochondrial homeostasis. (A-T) patient fibroblasts, wild-type fibroblasts treated with ATM inhibitor KU-55933,...

Ribonucleotide reductase catalyzes the production of deoxyribonucleoside diphosphates, precursors triphosphates for DNA synthesis. Mammalian ribonucleotide (RNR) is a tetramer consisting two non-identical homodimers, R1 and either R2 or p53R2, which are considered to be involved in replication repair, respectively. We have demonstrated that damage by doxorubicin cisplatin caused steady elevation protein p53(–/–) HCT-116 human colon carcinoma cells but induced degradation p53(+/+) cells. To...

PARP inhibitors exploit synthetic lethality to target epithelial ovarian cancer (EOC) with hereditary BRCA mutations and defects in homologous recombination repair (HRR). However, such an approach is limited a small subset of EOC patients compromised by restored HRR due secondary genes. Here, it was demonstrated that triapine, small-molecule inhibitor ribonucleotide reductase, enhances the sensitivity wild-type cells olaparib topoisomerase II etoposide. Triapine abolishes olaparib-induced...

Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency increased sensitivity chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved the HR pathway are thought strongly correlated favorable response treatment. Patients these mutations have better prognosis an improved rate. On other hand, non-HR...

Platinum resistance may be attributable to inherent or acquired proficiency in homologous recombination repair (HRR) epithelial ovarian cancer (EOC). The objective of this study was evaluate the efficacy small molecule inhibitor triapine disrupt HRR and sensitise BRCA wild-type EOC cells platinum-based combination therapy vitro vivo. sensitivity olaparib, cisplatin, carboplatin, doxorubicin, etoposide with evaluated by clonogenic survival assays. effects on activity were measured a DR-GFP...

PARP inhibitors target BRCA mutations and defective homologous recombination repair (HRR) for the treatment of epithelial ovarian cancer (EOC). However, HRR-proficient EOC with remains challenging. The objective this study was to determine whether combination triapine (ribonucleotide reductase inhibitor), cediranib (vascular endothelial growth factor receptor tyrosine kinase inhibitor olaparib synergized against wild-type in xenograft mouse models. In addition, mechanisms by which augmented...

Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation AKT pathway promotes platinum while inhibition sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus defect homologous recombination (HR) repair pathway, demonstrate greater clinical response to olaparib therapy than patients wild-type EOC. MK-2206, an allosteric inhibitor phosphorylation, variety cell types various anticancer agents currently undergoing phase II trials...

Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in production of deoxyribonucleoside triphosphates (dNTPs) required for replicative and repair DNA synthesis. Mammalian RNR is a heteromeric enzyme consisting primarily R1 R2 subunits during S phase cell cycle. We have shown previously that presence excess protects p53-deficient human colon cancer cells from cisplatin-induced damage replication stress. However, mode influenced by changes level subunit remained to be defined. In...

Although epithelial ovarian cancers (EOCs) are initially treated with platinum-based chemotherapy, EOCs vary in platinum responsiveness. Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive EOC cell lines is valuable for development of therapeutic strategies avoid inefficacy exploit sensitivity. TOV-21G devoid FANCF expression, OV-90 SKOV-3 were employed as examples platinum-sensitive, platinum-intermediate lines, respectively....

Abstract Poly ADP-ribose polymerase (PARP) inhibitors are promising targeted therapy for epithelial ovarian cancer (EOC) with BRCA mutations or defective homologous recombination (HR) repair. However, reversion of mutation and restoration HR repair in EOC lead to PARP inhibitor resistance reduced clinical efficacy inhibitors. We have previously shown that triapine, a small molecule ribonucleotide reductase (RNR), impaired sensitized repair-proficient In this study, we performed silico...

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, largely due to metastasis and drug resistant recurrences. Fifteen percent of tumors carry mutations in BRCA1 or BRCA2, rendering them vulnerable treatment with PARP inhibitors such as olaparib. Recent studies have shown that TGFβ can induce “BRCAness” BRCA wild-type cells. Given is a known driver epithelial mesenchymal transition (EMT), connection between EMT metastatic spread EOC other cancers, we asked if alter...

Ovarian cancer is the deadliest gynecologic malignancy in women, with a 46% five-year overall survival rate. The objective of study was to investigate effects non-homologous end-joining (NHEJ) genes on clinical outcomes ovarian patients. To determine if these act as prognostic biomarkers mortality and disease progression, expression profiles 48 NHEJ-associated were analyzed using an array statistical machine learning techniques: logistic regression models, decision trees, naive-Bayes, two...

Stress conditions associated with solid tumors lead to the formation of heterogeneous tumor cell subpopulations and insensitivity cancer chemotherapeutics. In this report, we show that EMT6 mouse mammary cells treated chemical stress, brefeldin A (BFA), or physiological hypoxia, develop resistance topoisomerase II (topoII) inhibitors teniposide etoposide. BFA hypoxia treatment did not alter intracellular drug concentrations, topoll protein levels, inhibit topoII activity. cause activation...

Abstract Background: Epithelial ovarian cancer (EOC) with homologous recombination (HR) deficiency is susceptible to PARP inhibitor therapy due synthetic lethality. Identification of the patient population for imperative reduce recurrence EOC and improve survival outcomes patients. Current biomarkers consist an array genes involved in HR repair pathway EOC, including BRCA1, BRCA2 PALB2. Through TCGA analysis, we found that lysine (K)-specific methyltransferase 2C (KMT2C) gene mutated 10.3%...

Abstract Background: Cancer immune evasion remains a major barrier in developing enduring therapies for epithelial ovarian cancer (EOC). Expression of programmed death-ligand 1 (PD-L1) is known its immunosuppressive role cancer, thus interferences to PD-L1 have shown marked efficacy against many advanced cancers. However, the mechanisms by which PD-L1-negative cancers evade response remain unelucidated. We found chemokine (C-C motif) ligand 5 (CCL5) and (C-X-C 10 (CXCL10) up-regulate EOC....

Millions of people globally are exposed to the proven human carcinogen arsenic at unacceptable levels in drinking water. In contrast, is a poor rodent carcinogen, requiring >100-fold higher doses for tumour induction, which may be explained by toxicokinetic differences between humans and mice. The ATP-binding cassette (ABC) transporter hABCC4 mediates cellular efflux diverse array metabolites, including GSH conjugate highly toxic monomethylarsonous acid (MMA

Abstract Objectives: Despite improvement in therapy, the majority of patients with ovarian cancer relapses and eventually succumbs to disease. Therefore, there is an urgent need for further understanding development progression cancer. It well established that phosphatidylinositol 3-kinase (Pi3k/Akt) pathway activated 70% cancers. We have previously shown AKT activity up regulated BRCA1 BRCA-2 deficient Epithelial-mesenchymal transition (EMT), a process by which cells acquire motility lose...