Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Acetylcysteine / pharmacology
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Animals
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Camptothecin / pharmacology
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Cell Cycle / drug effects
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Cell Death / drug effects
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Cell Hypoxia / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cytoprotection / drug effects
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DNA / metabolism
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DNA Topoisomerases, Type I / metabolism
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DNA Topoisomerases, Type II / metabolism
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Down-Regulation / drug effects
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Drug Screening Assays, Antitumor
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Ethidium / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism
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Humans
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry
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Isoquinolines / pharmacology*
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Mice
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reactive Oxygen Species / metabolism*
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Up-Regulation / drug effects
Substances
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Isoquinolines
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RNA, Messenger
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Reactive Oxygen Species
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cribrostatin 6
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DNA
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HMOX1 protein, human
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Heme Oxygenase-1
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DNA Topoisomerases, Type I
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DNA Topoisomerases, Type II
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Ethidium
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Acetylcysteine
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Camptothecin