title: Expression of histone H2AX phosphorylation and its potential to modulate adriamycin resistance in K562/A02 cell line.
abstract: DNA repair processes play a role in the development of drug resistance which represents a huge obstacle to leukemia chemotherapy. Histone H2AX phosphorylation (ser139) (γH2AX) occurs rapidly at the onset of DNA double strand break (DSB) and is critical to the regulation of DSB repair. If DNA repair is successful, cells exposed to anti-neoplastic drugs will keep entering the cycle and develop resistance to the drugs. In this study, we investigated whether γH2AX can be used as an indicator of tumor chemosensitivity and a potential target for enhancing chemotherapy. K562 and multi-drug resistant cell line K562/A02 were exposed to adriamycin (ADR) and γH2AX formed. Flow cytometry revealed that percentage of cells expressing γH2AX was increased in a dose-dependent manner and the percentage of K562/A02 cells was lower than that of K562 cells when treated with the same concentration of ADR. In order to test the potential of γH2AX to reverse drug resistance, K562/A02 cells were treated with PI3K inhibitor LY294002. It was found that LY249002 decreased ADR-induced γH2AX expression and increased the sensitivity of K562/A02 cells to ADR. Additionally, the single-cell gel electrophoresis assay and the Western blotting showed that LY249002 enhanced DSBs and decreased the expression of repair factor BRCA1. These results illustrate chemosensitivity can partly be measured by detecting γH2AX and drug resistance can be reversed by inhibiting γH2AX.
authors.affiliation: Department of Pediatrics, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Mei
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Huazhong University of Science and Technology, Wuhan, 430022, China. erke_xiehe@yahoo.com.cn.
authors.forename: Runming
authors.initials: R
authors.lastname: Jin
mesh_terms: D002867:Chromones / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation
chemical_list: D002867:Chromones; C468783:H2AX protein, human; D006657:Histones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004317:Doxorubicin