Abstract
The uncoupling proteins (UCPs) are mitochondrial carriers that modulate the energetic efficiency and, as a result, can lower superoxide levels. Here, we describe the discovery of a small-molecule inhibitor of the UCPs. Screening of potential UCP1 regulators led to the identification of chromane derivatives that inhibit its proton conductance. Members of the UCP family can act as a defense against oxidative stress and, thus, UCP2 plays a protective role in tumor cells. High UCP2 levels have been associated with chemoresistance. We demonstrate that chromanes also inhibit UCP2 and, in HT-29 human carcinoma cells, cause oxidative stress. The chromane derivatives can act synergistically with chemotherapeutic agents; for instance, they increase the toxicity of arsenic trioxide in HT-29 cells. These findings open a promising line in the development of novel anticancer agents.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arsenic Trioxide
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Arsenicals / pharmacology
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Biological Transport / drug effects
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Cell Respiration / drug effects
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Cell Survival / drug effects
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Chromans / chemistry
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Chromans / pharmacology*
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Drug Discovery*
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Drug Synergism
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Fatty Acids / metabolism
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HT29 Cells
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Humans
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Ion Channels / antagonists & inhibitors*
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Ion Channels / genetics
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Ion Channels / metabolism
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Liver / cytology
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Mice
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Mitochondrial Proteins / antagonists & inhibitors*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Oxidative Phosphorylation / drug effects
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Oxidative Stress / drug effects
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Oxides / pharmacology
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Protons
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Rats
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Saccharomyces cerevisiae / genetics
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Superoxides / metabolism
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Uncoupling Protein 1
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Uncoupling Protein 2
Substances
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Arsenicals
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Chromans
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Fatty Acids
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Ion Channels
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Mitochondrial Proteins
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Oxides
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Protons
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UCP1 protein, human
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UCP2 protein, human
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Ucp1 protein, mouse
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Ucp1 protein, rat
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Ucp2 protein, mouse
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Ucp2 protein, rat
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Uncoupling Protein 1
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Uncoupling Protein 2
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Superoxides
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Arsenic Trioxide