title: Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells.
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.
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan; Central Institute of Isotope Science, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasui
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Motofumi
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Bo
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagane
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Nishimura
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamori
authors.affiliation: Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Japan Science and Technology Agency, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Yamada
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: inanami@vetmed.hokudai.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Inanami
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000600:supply & distribution; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000503:physiopathology* / Q000532:radiotherapy / Q000628:therapy*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds
keywords: ATP; Cancer; Mitochondria; Radiation; Reactive oxygen species; Triphenylphosphonium