Abstract
D-(-)-Lentiginosine [(-)-4], the nonnatural enantiomer of the iminosugar indolizidine alkaloid L-(+)-lentiginosine, acts as apoptosis inducer on tumor cells of different origin, in contrast to its natural enantiomer. Although D-(-)-4 exhibited a proapoptotic activity towards tumor cells at level lower than the chemotherapeutic agent, SN38, it was less proapoptotic towards normal cells and less cytotoxic. Apoptosis induced by D-(-)-4 was caspase-dependent, as shown by the increased expression and activity of caspase-3 and -8 in treated cells, and by inhibition following treatment with the pan caspase inhibitor, ZVAD-FMK. This study highlighted how a natural iminosugar alkaloid and its synthetic enantiomer, which were simply known for their inhibition against a fungal glucoamylase, could behave in a complete different way when tested towards cell growth and death of cells of different origin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / chemical synthesis
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Alkaloids / chemistry
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Alkaloids / pharmacology*
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Amino Acid Chloromethyl Ketones / pharmacology
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Camptothecin / analogs & derivatives
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Camptothecin / pharmacology
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Caspase 3 / biosynthesis
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Caspase 3 / metabolism
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Caspase 8 / biosynthesis
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Caspase 8 / metabolism
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Caspase Inhibitors
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Glucan 1,4-alpha-Glucosidase / antagonists & inhibitors
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Humans
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Molecular Conformation
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Alkaloids
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Amino Acid Chloromethyl Ketones
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Antineoplastic Agents
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Caspase Inhibitors
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Enzyme Inhibitors
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SN38-Glu
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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lentiginosine
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Glucan 1,4-alpha-Glucosidase
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Caspase 3
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Caspase 8
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Camptothecin