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-l-oxy-piperidin (Tempol) with TPP+ (named."Mito-") were designed to inhibit the mitochondrial electron transport chain. Mito-(CH2)io-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). MlOT, 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. MIOT 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 TP13(+) is partly responsible for the observed radiosensitization. (C) 2017 Elsevier B.V. All rights reserved.