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Identification of novel mechanisms of action contributing to the biological activity of cytotoxic natural compounds
Identification of novel mechanisms of action contributing to the biological activity of cytotoxic natural compounds
Part I: Cephalostatin 1 is a potent marine cytotoxic compound reported to induce apoptosis without cytochrome c release and apoptosome formation. This work shows that, however, caspase-9 is essential for the induction of apoptosis. Cephalostatin 1 induces endoplasmic reticulum stress together with the activation of the ASK1/JNK cascade as well as caspase-4 and caspase-2, which act upstream of caspase-9 and are required for apoptosis. Part II: Sesquiterpene lactones are secondary plant metabolites with cytotoxic and anti-inflammatory activities. It was found that 11α,13-dihydrohelenalin acetate (α,β-unsaturated cyclopentenone) induces classical apoptosis whereas 7-hydroxycostunolide (α-methylene-γ-lactone) induces a novel form of cell death characterised by a fast and strong exposure of phosphatidylserine in agreement with a strong activation of phagocytosis in cocultured macrophages.
cephalostatin, apoptosis, caspase-4, caspase-9, sesquiterpene lactones, macrophage, phagocytosis
López Antón, Nancy
2006
Englisch
Universitätsbibliothek der Ludwig-Maximilians-Universität München
López Antón, Nancy (2006): Identification of novel mechanisms of action contributing to the biological activity of cytotoxic natural compounds. Dissertation, LMU München: Fakultät für Chemie und Pharmazie
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Abstract

Part I: Cephalostatin 1 is a potent marine cytotoxic compound reported to induce apoptosis without cytochrome c release and apoptosome formation. This work shows that, however, caspase-9 is essential for the induction of apoptosis. Cephalostatin 1 induces endoplasmic reticulum stress together with the activation of the ASK1/JNK cascade as well as caspase-4 and caspase-2, which act upstream of caspase-9 and are required for apoptosis. Part II: Sesquiterpene lactones are secondary plant metabolites with cytotoxic and anti-inflammatory activities. It was found that 11α,13-dihydrohelenalin acetate (α,β-unsaturated cyclopentenone) induces classical apoptosis whereas 7-hydroxycostunolide (α-methylene-γ-lactone) induces a novel form of cell death characterised by a fast and strong exposure of phosphatidylserine in agreement with a strong activation of phagocytosis in cocultured macrophages.