title: Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species.
abstract: Phloretin, a flavonoid present in various plants, has been reported to exert anticarcinogenic effects. However, the mechanism of its chemo-preventive effect on human glioblastoma cells is not fully understood. This study aimed to investigate the molecular mechanism of phloretin and its associated chemo-preventive effect in human glioblastoma cells. The results indicate that phloretin inhibited cell proliferation by inducing cell cycle arrest at the G0-G1 phase and induced apoptosis of human glioblastoma cells. Phloretin-induced cell cycle arrest was associated with increased expression of p27 and decreased expression of cdk2, cdk4, cdk6, cyclinD and cyclinE. Moreover, the PI3K/AKT/mTOR signaling cascades were suppressed by phloretin in a dose-dependent manner. In addition, phloretin triggered the mitochondrial apoptosis pathway and generated reactive oxygen species (ROS). This was accompanied by the up-regulation of Bax, Bak and c-PARP and the down-regulation of Bcl-2. The antioxidant agents N-acetyl-L-cysteine and glutathione weakened the effect of phloretin on glioblastoma cells. In conclusion, these results demonstrate that phloretin exerts potent chemo-preventive activity in human glioblastoma cells through the generation of ROS.
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Chenghe
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Lv
authors.initials: L
authors.lastname: Pu
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Haiqiang
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Teng
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Neuroscience, Neurosciences Research Institute, Peking University, Beijing, 100083, China.|Department of Neurobiology, Peking University Health Science Center, Beijing, 100083, China.
authors.forename: Albert Cheung Hoi
authors.initials: AC
authors.lastname: Yu
authors.affiliation: Key Laboratory of Neuroscience, Neurosciences Research Institute, Peking University, Beijing, 100083, China.|Department of Neurobiology, Peking University Health Science Center, Beijing, 100083, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Junlong
authors.initials: J
authors.lastname: Shu
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Hepatobiliary Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100043, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Kong
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Pan
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China. zhengl@bjmu.edu.cn.
authors.forename: Lemin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, 100034, China. ynhuang@sina.com.
authors.forename: Yining
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053453:Caspase 9 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010693:Phloretin / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D053453:Caspase 9; D051059:PTEN Phosphohydrolase; D010693:Phloretin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human; C506433:CASP9 protein, human
keywords: Apoptosis; Cell cycle arrest; Glioblastoma; Phloretin; Reactive oxygen species