title: Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells.
abstract: Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G₁/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G₁ and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway.
authors.affiliation: Department of Radiotherapy, the Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China. dingyushuang000@sina.com.
authors.forename: Yushuang
authors.initials: Y
authors.lastname: Ding
authors.affiliation: School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun 130012, China. wanghg13@mails.jlu.edu.cn.
authors.forename: Hongge
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun 130012, China. niujj14@mails.jlu.edu.cn.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Nephrology, the Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China. robertlmy@sina.com.
authors.forename: Manyu
authors.initials: M
authors.lastname: Luo
authors.affiliation: School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun 130012, China. yuzixin093@163.com.
authors.forename: Yangmei
authors.initials: Y
authors.lastname: Gou
authors.affiliation: Department of Nephrology, the Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China. miaolining55@163.com.
authors.forename: Lining
authors.initials: L
authors.lastname: Miao
authors.affiliation: School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun 130012, China. zouzh@jlu.edu.cn.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Radiotherapy, the Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China. jl.cheng@163.com.|Department of Thoracic Oncology, Jilin Provincial Cancer Hospital, 1018 Huguang Street, Changchun 130012, China. jl.cheng@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D038143:Inula / Q000737:chemistry; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045787:Sesquiterpenes, Eudesmane / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C453560:7,8-dihydro-8-oxoguanine; D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D017382:Reactive Oxygen Species; D045787:Sesquiterpenes, Eudesmane; D006147:Guanine; C004363:alantolactone
keywords: 8-oxoG; DNA damage; alantolactone; apoptosis; cell cycle arrest; colorectal cancer