Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 27, Pages 11400-11405Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0902204106
Keywords
drug resistance; pharmacology; selenium
Categories
Funding
- Cancerfonden ( the Swedish Cancer Society)
- Cancer och allergifonden ( the Swedish Cancer and Allergy Foundation)
- ALF ( Stockholm County Council)
- Radiumhemmets forskningsfonder
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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.
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