Journal article
Extracellular thiol-assisted selenium uptake dependent on the x(c)(-) cystine transporter explains the cancer-specific cytotoxicity of selenite
The selenium salt selenite (SeO32-) is cytotoxic in low to moderate concentrations, with a remarkable specificity for cancer cells resistant to conventional chemotherapy. Our data show that selenium uptake and accumulation, rather than intracellular events, are crucial to the specific selenite cytotoxicity observed in resistant cancer cells.
We show that selenium uptake depends on extracellular reduction, and that the extracellular environment is a key factor specific to selenite cytotoxicity. The extracellular reduction is mediated by cysteine, and the efficacy is determined by the uptake of cystine by the x(c)(-) antiporter and secretion of cysteine by multidrug resistance proteins, both of which are frequently over-expressed by resistant cancer cells.
This mechanism provides molecular evidence for the existence of an inverse relationship between resistance to conventional chemotherapy and sensitivity to selenite cytotoxicity, and highlights the great therapeutic potential in treating multidrug-resistant cancer.
Language: | English |
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Publisher: | National Academy of Sciences |
Year: | 2009 |
Pages: | 11400-11405 |
ISSN: | 10916490 and 00278424 |
Types: | Journal article |
DOI: | 10.1073/pnas.0902204106 |
ATP Binding Cassette Transporter, Subfamily B, Member 1 Amino Acid Transport System y+ Antiporters Cell Death Cell Line, Tumor Cystine Drug Resistance, Neoplasm Extracellular Space Glutathione Humans Lung Neoplasms Models, Biological Organoselenium Compounds Oxidation-Reduction SLC7A11 protein, human Selenium Sodium Selenite Sulfhydryl Compounds selenocystine selenodiglutathione