Development of Chromanes as Novel Inhibitors of the Uncoupling Proteins

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (208 K)Download as PowerPoint slideHighlights► Uncoupling proteins (UCPs) are involved in cellular protection against oxidative stress ► Chromane derivatives have been identified as novel inhibitors of the proton transport activity of the UCPs ► Inhibition of UCP2 in cancer cells increases the levels of reactive oxygen species ► Chromane derivatives increase the efficacy of antitumor drugs