title: Arsenic trioxide induces ROS activity and DNA damage, leading to G0/G1 extension in skin fibroblasts through the ATM-ATR-associated Chk pathway.
abstract: Arsenic (As) toxicity is a global health problem, affecting millions of people. Exposure to arsenic, mostly via drinking water, has been associated with cancer of skin, lungs, and blood, in addition to several kinds of skin lesions. The present study focused on the effect of arsenic trioxide (As2O3) on normal skin fibroblast cells. Specifically, the effect of As2O3on ROS generation and oxidative stress was investigated. Proteins involved in the DNA damage signaling pathway and cell cycle were also studied. As2O3induced the generation of intracellular ROS. Immunohistochemistry analysis revealed a dose-dependent increase in the number of 8-OHdG-positive cells, an indication of oxidative stress. Cell cycle analysis by flow cytometry demonstrated that As2O3caused a significant percentage of cells to accumulate in the G0/G1 phase with a concomitant reduction in the S phase. Increases in the activated forms of DNA damage signaling proteins, ATM and ATR, and their effector molecules, Chk2 and p53, were also observed. In addition, expression of oncogene p21 was also increased. The study shows that exposure of normal skin fibroblast cells to As2O3could lead to cell cycle arrest through ATM/ATR and DNA damage signaling pathways. In conclusion, we report here that arsenic trioxide increases cellular oxidative stress leading to shift in cell cycle and leads to DNA damage through ATM/ATR and the CHK-dependent signaling pathway.
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Jutapon
authors.initials: J
authors.lastname: Chayapong
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Harishkumar
authors.identifier: http://orcid.org/0000-0002-7143-4821
authors.initials: H
authors.lastname: Madhyastha
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Radha
authors.initials: R
authors.lastname: Madhyastha
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Queen Intan
authors.initials: QI
authors.lastname: Nurrahmah
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Narantsog
authors.initials: N
authors.lastname: Choijookhuu
authors.affiliation: Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hishikawa
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan. masugi@med.miyazaki-u.ac.jp.
authors.forename: Masugi
authors.initials: M
authors.lastname: Maruyama
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D002455:Cell Division; D045744:Cell Line, Tumor; D004249:DNA Damage; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts; D006801:Humans; D010087:Oxides / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001152:Arsenicals; D004785:Environmental Pollutants; D010087:Oxides; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; Cell cycle arrest; DNA damage; G0/G1