title: Anti-Oncogenic gem-Dihydroperoxides Induce Apoptosis in Cancer Cells by Trapping Reactive Oxygen Species.
abstract: Organic gem-dihydroperoxides (DHPs) and their derived peroxides have attracted a great deal of attention as potential anti-cancer agents. However, the precise mechanism of their inhibitory effect on tumors is unknown. To determine the mechanism of the inhibitory effects of DHPs, we examined the effects of DHPs on leukemia K562 cells. As a result, certain DHPs used in this study exhibited growth-inhibitory activity according to a clear structure-activity relationship. The most potent DHP, 12AC3O, induced apoptosis in K562 cells, but not in peripheral blood monocytes (PBMCs) or fibroblast cells. 12AC3O induced apoptosis through the intrinsic mitochondrial pathway and thereafter through the extrinsic pathway. The activity of the former pathway was partly attenuated by a JNK inhibitor. Interestingly, 12AC3O induced apoptosis by trapping a large amount of ROS, leading to an extremely lower intracellular ROS level compared with that in the cells in the steady-state condition. These results suggest that an appropriate level of intracellular ROS was necessary for the maintenance of cancer cell growth. DHPs may have a potential to be a novel anti-cancer agent with minimum adverse effects on normal cells.
authors.affiliation: United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. t3125010@edu.gifu-u.ac.jp.|Graduate School of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. t3125010@edu.gifu-u.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuranaga
authors.affiliation: United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. namiyamada80@gmail.com.
authors.forename: Nami
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan. vo.ov.happy@gmail.com.
authors.forename: Maiko
authors.initials: M
authors.lastname: Kashiwaya
authors.affiliation: Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan. 106028@gifu-pu.ac.jp.
authors.forename: Moeko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan. Cui.Lei@otsuka.jp.
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.affiliation: United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. t3501001@edu.gifu-u.ac.jp.
authors.forename: Minami
authors.initials: M
authors.lastname: Kumazaki
authors.affiliation: United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. t3501002@edu.gifu-u.ac.jp.
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. t3125016@edu.gifu-u.ac.jp.|Graduate School of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. t3125016@edu.gifu-u.ac.jp.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Sugito
authors.affiliation: United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. sur144@poh.osaka-med.ac.jp.
authors.forename: Kohei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. an1006@art.osaka-med.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan. tnakayama@gifu-pu.ac.jp.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan. uno@gifu-pu.ac.jp.
authors.forename: Bunji
authors.initials: B
authors.lastname: Uno
authors.affiliation: Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan. itoha@gifu-pu.ac.jp.
authors.forename: Akichika
authors.initials: A
authors.lastname: Itoh
authors.affiliation: United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. yakao@gifu-u.ac.jp.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases
keywords: JNK/MAPK; ROS; apoptosis; cancer cell; dihydroperoxide