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

Hironobu Yasui, Kumiko Yamamoto, Motofumi Suzuki, Yuri Sakai, Tomoki Bo, Masaki Nagane, Eri Nishimura, Tohru Yamamori, Osamu Inanami, Ken-Ichi Yamada, Toshihide Yamasaki

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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.

Original languageEnglish
Pages (from-to)160-167
Number of pages8
JournalCancer Letters
Volume390
DOIs
Publication statusPublished - Apr 1 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Yasui, H., Yamamoto, K., Suzuki, M., Sakai, Y., Bo, T., Nagane, M., Nishimura, E., Yamamori, T., Inanami, O., Yamada, K-I., & Yamasaki, T. (2017). Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells. Cancer Letters, 390, 160-167. https://doi.org/10.1016/j.canlet.2017.01.006