Identification of novel mechanisms of action contributing to the biological activity of cytotoxic natural compounds

López Antón, Nancy (2006): Identification of novel mechanisms of action contributing to the biological activity of cytotoxic natural compounds. Dissertation, LMU München: Faculty of Chemistry and Pharmacy

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.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: cephalostatin, apoptosis, caspase-4, caspase-9, sesquiterpene lactones, macrophage, phagocytosis
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 540 Chemistry and allied sciences
• Faculties: Faculty of Chemistry and Pharmacy
• Language: English
• Date of oral examination: 3. April 2006
• 1. Referee: Vollmar, Angelika
• Signature of the printed copy: 0001/UMC 15468