Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human checkpoint kinase 1 (Chk1) is an essential kinase required to preserve genome stability. Here, we show that Chk1 inhibition by two distinct drugs, UCN-01 and CEP-3891, or by Chk1 small interfering RNA (siRNA) leads to phosphorylation of ATR targets. Chk1-inhibition triggered rapid, pan-nuclear phosphorylation of histone H2AX, p53, Smc1, replication protein A, and Chk1 itself in human S-phase cells. These phosphorylations were inhibited by ATR siRNA and caffeine, but they occurred independently of ATM. Chk1 inhibition also caused an increased initiation of DNA replication, which was accompanied by increased amounts of nonextractable RPA protein, formation of single-stranded DNA, and induction of DNA strand breaks. Moreover, these responses were prevented by siRNA-mediated downregulation of Cdk2 or the replication initiation protein Cdc45, or by addition of the CDK inhibitor roscovitine. We propose that Chk1 is required during normal S phase to avoid aberrantly increased initiation of DNA replication, thereby protecting against DNA breakage. These results may help explain why Chk1 is an essential kinase and should be taken into account when drugs to inhibit this kinase are considered for use in cancer treatment.
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PMID:Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. 1583 61

DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.
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PMID:Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro. 2443 51

The present study was designed to identify conditions that could increase the sensitivity of resistant cancer cells to antimitotic drugs. We investigated whether a Janus kinase 2 (JAK2) inhibitor used in clinical trials, XL019, sensitizes antimitotic drug-resistant KBV20C cells. XL019 reduced cellular viability and increased apoptosis in vincristine-treated KBV20C cells, independently of the JAK/signal transducer and activator of transcription (STAT) pathway. Based on the ATP-binding cassette protein B1 [ABCB1, P-glycoprotein (P-gp)] inhibitory assay, we demonstrated that XL019 functions as a P-gp inhibitor in drug-resistant KBV20C cells. Considering that another JAK2 inhibitor, CEP-33779, also inhibited P-gp and sensitized drug-resistant cancer cells in a previous study, we concluded that JAK2 inhibitors can be used as P-gp inhibitors in drug-resistant cancer cells. Fluorescence-activated cell sorting, western blot, and annexin V analyses were used to further investigate the mechanism of action of XL019 in vincristine-treated KBV20C cells. XL019 induced early apoptosis of KBV20C cells in response to vincristine treatment via increased G2 phase arrest. Moreover, G2 phase arrest and apoptosis of cells co-treated with vincristine and XL019 resulted from the up-regulation of phosphorylated retinoblastoma protein (pRb), p21, and the DNA-damage protein, phosphorylated H2A histone family, member X (pH2AX). Additionally, the P-gp-inhibitory effect of XL019 was less than that of CEP-33779, and a more than 2-fold higher dose was required to sensitize vincristine-treated KBV20C cells. Furthermore, lower doses of XL019 were required to sensitize KBV20C cells to a degree similar to that obtained with the established P-gp inhibitor verapamil, suggesting that XL019 has higher specificity than verapamil. Our results showed that JAK2 inhibitors inhibited P-gp action via a direct binding mechanism, which was similar to that of verapamil. These findings indicate that JAK2 inhibitors may be promising therapeutics for the treatment of cancer that is resistant to antimitotic drugs.
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PMID:P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression. 2918 54