Extracellular thiol-assisted selenium uptake dependent on the x(c)(-) cystine transporter explains the cancer-specific cytotoxicity of selenite

E. Olm, A. P. Fernandes, C. Hebert, A. K. Rundlof, Erik Huusfeldt Larsen, O. Danielsson, M. Bjornstedt

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number27
Pages (from-to)11400-11405
ISSN0027-8424
DOIs
Publication statusPublished - 2009

Keywords

  • selenium
  • drug resistance
  • pharmacology

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