title: Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS.
abstract: Parthanatos is a new form of programmed cell death that is regulated by hyper-activated PARP-1, and is emerging as a new strategy to kill cancer cells. Deoxypodophyllotoxin (DPT) is a natural chemical that is found to induce cancer cell death, in which the role of parthanatos is unknown. Thus, we investigated this issue in this study by using glioma cell lines and mice model of xenograft glioma. We found that DPT induced glioma cell death in vitro and inhibited the growth of xenograft glioma in vivo, which was accompanied with parthanatos-related biochemical events including expressional upregulation of PARP-1, cytoplasmic accumulation of PAR polymer, and nuclear translocation of AIF. In vitro study revealed that genetic knockdown of PARP-1 with small interfering RNA attenuated DPT-induced elevation in the cytoplasmic PAR-polymer and the nuclear AIF, as well as protected glioma cells against the toxicity of DPT. Further, antioxidant NAC, as well as PARP-1 inhibitor 3AB, not only alleviated the overproduction of ROS caused by DPT, but also reversed the above-mentioned biochemical events, maintained mitochondrial membrane potential and rescued glioma cells death. Therefore, we demonstrated that deoxypodophyllotoxin triggered parthanatos in glioma cells via induction of excessive ROS.
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Diandong
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China; Department of Neurology, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Tianfei
authors.initials: T
authors.lastname: Luo
authors.affiliation: Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China; Department of Neurology, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Jiachun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Breast Surgery, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Hongyao
authors.initials: H
authors.lastname: Jia
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
authors.forename: Guangfan
authors.initials: G
authors.lastname: Chi
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun 130021, China. Electronic address: gepf@jlu.edu.cn.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Ge
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018384:Oxidative Stress / Q000187:drug effects*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D004365:Drugs, Chinese Herbal; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; C014451:deoxypodophyllotoxin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011034:Podophyllotoxin
keywords: Deoxypodophyllotoxin; Glioma; PARP-1; Parthanatos; ROS