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- Title
Effect of DNA damage response by quinazolinone analogue HMJ-38 on human umbilical vein endothelial cells: Evidence for γH2A.X and DNA-PK-dependent pathway.
- Authors
Chiang, J-H; Yang, J-S; Lu, C-C; Hour, M-J; Liu, K-C; Lin, J-H; Lee, T-H; Chung, J-G
- Abstract
The present study aims to explore the mechanism of quinazolinone analogue HMJ-38-induced DNA damage in endothelial cells in vitro. We attempt to evaluate the antiangiogenetic response utilizing human umbilical vein endothelial cells (HUVECs). Herein, the results demonstrated that HMJ-38 incubation triggered DNA damage behavior and showed a longer DNA migration in HUVECs based on the comet assay and the analysis of DNA agarose gel electrophoresis to contact DNA smears. We further gained to determine a marker of DNA double strand breaks, phosphorylated histone H2A.X (Ser139) (γH2A.X), in HMJ-38-treated HUVECs by flow cytometry and Western blotting assay. We consider that HMJ-38 has caused an increase in γH2A.X, and DNA damage seemed to mediate through DNA-dependent serine/threonine protein kinase (DNA-PK) binding to Ku70/Ku80 as well as advanced activated p-Akt (Ser473) and stimulated phosphorylated glycogen synthase kinase-3β (p-GSK-3β) conditions in HUVECs. Importantly, the effect of above DNA damage response was prevented by N-acetyl-l-cysteine (a reactive oxygen species scavenger), and NU7026 (a DNA-PK inhibitor) could attenuate DNA-PK catalytic subunit and phosphorylation of H2A.X on Ser139 expression in comparison with HMJ-38 alone treated HUVECs. Therefore, HMJ-38-provoked DNA damage stress in HUVECs probably led to the activation of γH2A.X/DNA-PK/GSK-3β signaling. In summary, our novel finding provides more information addressing the pharmacological approach of newly synthesized HMJ-38 for further development and therapeutic application in antiangiogenetic effect of cancer chemotherapy.
- Subjects
QUINAZOLINONES; UMBILICAL cord diseases; CANCER chemotherapy; PHOSPHORYLATION; ELECTROPHORESIS
- Publication
Human & Experimental Toxicology, 2014, Vol 33, Issue 6, p590
- ISSN
0960-3271
- Publication type
Article
- DOI
10.1177/0960327113504791