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Cribrostatin 6 induces death in cancer cells through a reactive oxygen species (ROS)-mediated mechanism

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Summary

Cribrostatin 6 is a quinone-containing natural product that induces the death of cancer cell lines in culture, and its mechanism of action and scope of activity are unknown. Here we show that cribrostatin 6 has broad anticancer activity, potently inducing apoptotic cell death that is not preceded by any defined cell cycle arrest. Consistent with this data, we find that cribrostatin 6 treated cells have large amounts of reactive oxygen species (ROS) and, based on transcript profiling experiments and other data, this ROS generation is likely the primary mechanism by which cribrostatin 6 induces apoptosis. Given the success of certain ROS producers as anticancer agents, cribrostatin 6 has potential as a novel chemotherapeutic agent.

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Acknowledgements

We would like to thank Justin Lamb (Broad Institute) for advice regarding use of the Connectivity Map database, the Keck facility at the University of Illinois for performing the microarray experiment and data processing, Russel J. Mumper (U. Kentucky) for the kind gift of the HL-60 VCR cell line, Joseph S. Bair (UIUC) for synthesis of tirapazamine, and Dr. Benjamin J. Leslie (UIUC) for preliminary HL-60 VCR assays. Funding was provided by the University of Illinois.

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  1. Department of Chemistry, Roger Adams Laboratory, University of Illinois, 600 S Mathews Ave, Urbana, IL, 61801, USA

    Mirth T. Hoyt, Rahul Palchaudhuri & Paul J. Hergenrother

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  1. Mirth T. Hoyt
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Correspondence to Paul J. Hergenrother.

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Materials and methods, spectral data for all new compounds, and pathway diagrams based on transcript profiling experiments. (PDF 2083 kb)

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Hoyt, M.T., Palchaudhuri, R. & Hergenrother, P.J. Cribrostatin 6 induces death in cancer cells through a reactive oxygen species (ROS)-mediated mechanism. Invest New Drugs 29, 562–573 (2011). https://doi.org/10.1007/s10637-010-9390-x

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