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Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells.
- Source :
-
Cancer letters [Cancer Lett] 2017 Apr 01; Vol. 390, pp. 160-167. Date of Electronic Publication: 2017 Jan 16. - Publication Year :
- 2017
-
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 <superscript>+</superscript> ) cation derivatives and related compounds such as 4-hydroxy-2,2,6,6-tetramethyl-1-oxy-piperidin (Tempol) with TPP <superscript>+</superscript> (named "Mito-") were designed to inhibit the mitochondrial electron transport chain. Mito-(CH <subscript>2</subscript> ) <subscript>10</subscript> -Tempol (M10T) and its derivatives, Mito-(CH <subscript>2</subscript> ) <subscript>5</subscript> -Tempol (M5T), Mito-(CH <subscript>2</subscript> ) <subscript>10</subscript> -Tempol-Methyl (M10T-Me), Mito-C <subscript>10</subscript> H <subscript>21</subscript> (M10), and C <subscript>10</subscript> H <subscript>21</subscript> -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 <superscript>+</superscript> 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 <superscript>+</superscript> is partly responsible for the observed radiosensitization.<br /> (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Subjects :
- Antineoplastic Agents pharmacology
Antineoplastic Agents supply & distribution
Cell Line, Tumor
Drug Synergism
Energy Metabolism drug effects
HeLa Cells
Humans
Hydrophobic and Hydrophilic Interactions
Mitochondria metabolism
Neoplasms radiotherapy
Organophosphorus Compounds chemistry
Cell Death drug effects
Mitochondria drug effects
Neoplasms physiopathology
Neoplasms therapy
Organophosphorus Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 390
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 28093283
- Full Text :
- https://doi.org/10.1016/j.canlet.2017.01.006