title: The role of the ATM/Chk/P53 pathway in mediating DNA damage in hand-foot syndrome induced by PLD.
abstract: Pegylated liposomal doxorubicin (PLD) has been approved to treat patients with various types of cancers because it rarely caused side effects, such as cardiotoxicity, in comparison to doxorubicin, but it frequently results in hand-foot syndrome (HFS). This may affect the quality of life and require a reduction in the PLD dose. The pathophysiology of HFS was not well understood. This study was aimed at exploring the mechanism of HFS induced by PLD. We compared the effects of different doses of PLD on the proliferation inhibition and apoptosis in vitro in HaCaT cells and analyzed the skin changes and skin cell DNA damage in vivo using a zebrafish model. The results suggested that very low doses of PLD show a proliferation inhibition (cell cycle arrest at G2/M phase) and an apoptosis phenotype characterized by the ATM/Chk/P53 pathway that mediates DNA damage in vitro in HaCaT cells. In addition, PLD enhanced zebrafish skin pigmentation from the head to the trunk and induced DNA damage (phospho-H2AX staining) and cell death in the skin of zebrafish. The results of the present study suggested potential applications to provide a better understanding of the apoptosis of PLD-treated skin cells and described a simple methodology for detecting a PLD-induced DNA damage response in zebrafish, which may be helpful in preventing and treating HFS.
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Long
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Junnai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Wei
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Mingfu
authors.initials: M
authors.lastname: Wu
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Shuangmei
authors.initials: S
authors.lastname: Ye
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: liuzhu38@126.com.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: qlgao@tjh.tjmu.edu.cn.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000633:toxicity; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D060831:Hand-Foot Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Apoptosis; HaCaT cell; Pegylated liposomal doxorubicin (PLD); Zebrafish