Cytotoxic effects and apoptotic signalling mechanisms of the sesquiterpenoid euplotin C, a secondary metabolite of the marine ciliate Euplotes crassus, in tumour cells

• Published in: Apoptosis (London) Vol. 11; no. 5; pp. 829 - 843
• Main Authors: Cervia, D, Martini, D, Garcia-Gil, M, Di Giuseppe, G, Guella, G, Dini, F, Bagnoli, P
• Format: Journal Article
• Language: English
• Published: Netherlands Springer Nature B.V 01.05.2006
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Calcium - analysis; Calcium - metabolism; Caspase 3; Caspases - analysis; Caspases - metabolism; Cells; Cells, Cultured; Chromatography, High Pressure Liquid; Cytochrome; Cytosol - metabolism; DNA Fragmentation - drug effects; Euplotes - chemistry; Euplotes - classification; Euplotes - metabolism; Euplotes crassus; Mass Spectrometry; Metabolites; Mice; Microorganisms; Molecular Structure; Molecular Weight; PC12 Cells; Pituitary Neoplasms - pathology; Proteins; Rats; Sesquiterpenes - chemistry; Sesquiterpenes - isolation & purification; Sesquiterpenes - toxicity; Spectrometry, Mass, Electrospray Ionization
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-006-5700-3

Most antitumour agents with cytotoxic properties induce apoptosis. The lipophilic compound euplotin C, isolated from the ciliate Euplotes crassus, is toxic to a number of different opportunistic or pathogenic microorganisms, although its mechanism of action is currently unknown. We report here that euplotin C is a powerful cytotoxic and pro-apoptotic agent in mouse AtT-20 and rat PC12 tumour-derived cell lines. In addition, we provide evidence that euplotin C treatment results in rapid activation of ryanodine receptors, depletion of Ca2+ stores in the endoplasmic reticulum (ER), the release of cytochrome c from the mitochondria, activation of caspase-12, and activation of caspase-3, leading to apoptosis. Intracellular Ca2+ overload is an early event which induces apoptosis and is parallelled by ER stress and the release of cytochrome c, whereas caspase-12 may be activated by euplotin C at a later stage in the apoptosis pathway. These events, either independently or concomitantly, lead to the activation of the caspase-3 and its downstream effectors, triggering the cell to undergo apoptosis. These results demonstrate that euplotin C may be considered for the design of cytotoxic and pro-apoptotic new drugs.