Please use this identifier to cite or link to this item: https://doi.org/10.1074/jbc.M111.278390
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dc.titleChemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target
dc.contributor.authorFedeles, B.I.
dc.contributor.authorZhu, A.Y.
dc.contributor.authorYoung, K.S.
dc.contributor.authorHillier, S.M.
dc.contributor.authorProffitt, K.D.
dc.contributor.authorEssigmann, J.M.
dc.contributor.authorCroy, R.G.
dc.date.accessioned2016-06-01T10:29:04Z
dc.date.available2016-06-01T10:29:04Z
dc.date.issued2011-10-30
dc.identifier.citationFedeles, B.I., Zhu, A.Y., Young, K.S., Hillier, S.M., Proffitt, K.D., Essigmann, J.M., Croy, R.G. (2011-10-30). Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target. Journal of Biological Chemistry 286 (39) : 33910-33920. ScholarBank@NUS Repository. https://doi.org/10.1074/jbc.M111.278390
dc.identifier.issn00219258
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/124776
dc.description.abstractThe antitumor agent 11β (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive prostate cancer cells in vitro; it also strongly prevents growth of LNCaP xenografts in mice. The present study describes the unexpectedly strong activity of 11β against the AR-negative HeLa cells, both in cell culture and tumor xenografts, and uncovers a new mechanism of action that likely explains this activity. Cellular fractionation experiments indicated that mitochondria are the major intracellular sink for 11β; flow cytometry studies showed that 11βexposure rapidly induced oxidative stress, mitochondria being an important source of reactive oxygen species (ROS). Additionally, 11β inhibited oxygen consumption both in intact HeLa cells and in isolated mitochondria. Specifically, 11β blocked uncoupled oxygen consumption when mitochondria were incubated with complex I substrates, but it had no effect on oxygen consumption driven by substrates acting downstream of complex I in the mitochondrial electron transport chain. Moreover, 11β enhanced ROS generation in isolated mitochondria, suggesting that complex I inhibition is responsible for ROS production. At the cellular level, the presence of antioxidants (N-acetylcysteine or vitamin E) significantly reduced the toxicity of 11β, implicating ROS production as an important contributor to cytotoxicity. Collectively, our findings establish complex I inhibition andROSgeneration as a new mechanism of action for 11β, which supplements conventional DNA adduct formation to promote cancer cell death. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1074/jbc.M111.278390
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentDUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE
dc.description.doi10.1074/jbc.M111.278390
dc.description.sourcetitleJournal of Biological Chemistry
dc.description.volume286
dc.description.issue39
dc.description.page33910-33920
dc.description.codenJBCHA
dc.identifier.isiut000295159200023
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