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Int. J. Mol. Sci. 2016, 17(1), 71;

Anti-Oncogenic gem-Dihydroperoxides Induce Apoptosis in Cancer Cells by Trapping Reactive Oxygen Species

United Graduate School of Drug Discovery and Information Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Graduate School of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
Author to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 5 November 2015 / Revised: 31 December 2015 / Accepted: 31 December 2015 / Published: 8 January 2016
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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. View Full-Text
Keywords: apoptosis; ROS; dihydroperoxide; JNK/MAPK; cancer cell apoptosis; ROS; dihydroperoxide; JNK/MAPK; cancer cell

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Kuranaga, Y.; Yamada, N.; Kashiwaya, M.; Nakamura, M.; Cui, L.; Kumazaki, M.; Shinohara, H.; Sugito, N.; Taniguchi, K.; Ito, Y.; Nakayama, T.; Uno, B.; Itoh, A.; Akao, Y. Anti-Oncogenic gem-Dihydroperoxides Induce Apoptosis in Cancer Cells by Trapping Reactive Oxygen Species. Int. J. Mol. Sci. 2016, 17, 71.

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