Abstract
Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G2-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects*
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / physiology*
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Bcl-2-Like Protein 11
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Cell Cycle / drug effects
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Cell Division / drug effects
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Fatty Alcohols / isolation & purification
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Fatty Alcohols / pharmacology*
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G2 Phase / drug effects
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Humans
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Lactation
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Mammary Glands, Animal / drug effects
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Mammary Glands, Animal / pathology
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Membrane Proteins / biosynthesis
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Membrane Proteins / physiology*
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Mice
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Microtubules / drug effects
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Microtubules / metabolism
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Persea / chemistry*
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Plant Leaves / chemistry
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Transfection
Substances
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Antineoplastic Agents, Phytogenic
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Fatty Alcohols
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Membrane Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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persin