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Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells

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Title: Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells
Authors: Yasui, Hironobu Browse this author →KAKEN DB
Yamamoto, Kumiko Browse this author
Suzuki, Motofumi Browse this author
Sakai, Yuri Browse this author
Bo, Tomoki Browse this author
Nagane, Masaki Browse this author
Nishimura, Eri Browse this author
Yamamori, Tohru Browse this author →KAKEN DB
Yamasaki, Toshihide Browse this author
Yamada, Ken-ichi Browse this author
Inanami, Osamu Browse this author →KAKEN DB
Keywords: ATP
Reactive oxygen species
Issue Date: 1-Apr-2017
Publisher: Elsevier
Journal Title: Cancer Letters
Volume: 390
Start Page: 160
End Page: 167
Publisher DOI: 10.1016/j.canlet.2017.01.006
PMID: 28093283
Abstract: It has recently been reported that radiation enhances mitochondrial energy metabolism in various tumor cell lines. To examine how this radiation-induced alteration in mitochondrial function influences tumor cell viability, various lipophilic triphenylphosphonium (TPP+) cation derivatives and related compounds such as 4-hydroxy-2,2,6,6-tetramethyl-1-oxy-piperidin (Tempol) with TPP+ (named “Mito-”) were designed to inhibit the mitochondrial electron transport chain. Mito-(CH2)10-Tempol (M10T) and its derivatives, Mito-(CH2)5-Tempol (M5T), Mito-(CH2)10-Tempol-Methyl (M10T-Me), Mito-C10H21 (M10), and C10H21-Tempol (10T), were prepared. In HeLa human cervical adenocarcinoma cells and A549 human lung carcinoma cells, the fractional uptake of the compound into mitochondria was highest among the TTP+ analogs conjugated with Tempol (M10T, M5T, and 10T). M10T, M10T-Me, and M10 exhibited strong cytotoxicity and enhanced X-irradiation-induced reproductive cell death, while 10T and M5T did not. Furthermore, M10T, M10T-Me, and M10 decreased basal mitochondrial membrane potential and intracellular ATP. M10T treatment inhibited X-ray-induced increases in ATP production. These results indicate that the TPP cation and a long hydrocarbon linker are essential for radiosensitization of tumor cells. The reduction in intracellular ATP by lipophilic TPP+ is partly responsible for the observed radiosensitization. (c) 2017 Elsevier Ireland Ltd. All rights reserved.
Rights: © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 稲波 修

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