Human malignant pleural mesothelioma (MPM) is a dreadful disease and there is still no standard therapy available for a consistent therapeutic approach. This research is aimed at the evaluation of the potential therapeutic effect of a specific nicotinic receptor (nAChR) antagonist, namely alpha-Cobratoxin (alpha-CbT). Its effectiveness was tested in mesothelioma cell lines and in primary mesothelioma cells in vitro, as well as in vivo, in orthotopically xenotransplanted NOD/SCID mice. Cells showed alpha7-nAChR expression and their growth was significantly inhibited by alpha-CbT. Severe induction of apoptosis was observed after exposure to alpha-CbT [IC(80-90)]. Apoptosis was characterised by: change in mitochondrial potential, caspase-3 cleavage, down-regulation of mRNA and protein for survivin, XIAP, IAP1, IAP2 and Bcl-XL, inhibition by caspase-3 inhibitor. In vivo, the alpha-CbT acute LD(50) was 0.15 mg/kg. The LD(100) [0.24 mg/kg] induced fatal respiratory failure and massive kidney necrosis. Phase II experiments with 0.12 ng/kg alpha-CbT (1/1000 of LD(10)) were done in 53 xenotransplanted mice, inhibiting tumour development as confirmed by chest X-ray examinations, autopsy and microscopical findings. The growth of human proliferating T lymphocytes and of mesothelial cells in primary culture was not affected by alpha-CbT. Non-immunogenic derivatives of the alpha-CbT molecule need to be developed for possible human use.

Catassi, A., Paleari, L., Dennis, S., Sessa, F., Dominioni, L., Emanuela, O., Cilli, M., Vacca, P., Mingari, M., Gaudino, G., Bertino, P., Paolucci, M., Calcaterra, A., Cesario, A., Granone, P., Costa, R., Ciarlo, M., Alama, A., Russo, P., Targeting alpha7-nicotinic receptor for the treatment of pleural mesothelioma., <<EUROPEAN JOURNAL OF CANCER>>, 2008; (Ottobre): 2296-2311 [http://hdl.handle.net/10807/5462]

Targeting alpha7-nicotinic receptor for the treatment of pleural mesothelioma.

Cesario, Alfredo;Granone, Pierluigi;Costa, Roberta;
2008

Abstract

Human malignant pleural mesothelioma (MPM) is a dreadful disease and there is still no standard therapy available for a consistent therapeutic approach. This research is aimed at the evaluation of the potential therapeutic effect of a specific nicotinic receptor (nAChR) antagonist, namely alpha-Cobratoxin (alpha-CbT). Its effectiveness was tested in mesothelioma cell lines and in primary mesothelioma cells in vitro, as well as in vivo, in orthotopically xenotransplanted NOD/SCID mice. Cells showed alpha7-nAChR expression and their growth was significantly inhibited by alpha-CbT. Severe induction of apoptosis was observed after exposure to alpha-CbT [IC(80-90)]. Apoptosis was characterised by: change in mitochondrial potential, caspase-3 cleavage, down-regulation of mRNA and protein for survivin, XIAP, IAP1, IAP2 and Bcl-XL, inhibition by caspase-3 inhibitor. In vivo, the alpha-CbT acute LD(50) was 0.15 mg/kg. The LD(100) [0.24 mg/kg] induced fatal respiratory failure and massive kidney necrosis. Phase II experiments with 0.12 ng/kg alpha-CbT (1/1000 of LD(10)) were done in 53 xenotransplanted mice, inhibiting tumour development as confirmed by chest X-ray examinations, autopsy and microscopical findings. The growth of human proliferating T lymphocytes and of mesothelial cells in primary culture was not affected by alpha-CbT. Non-immunogenic derivatives of the alpha-CbT molecule need to be developed for possible human use.
Inglese
Catassi, A., Paleari, L., Dennis, S., Sessa, F., Dominioni, L., Emanuela, O., Cilli, M., Vacca, P., Mingari, M., Gaudino, G., Bertino, P., Paolucci, M., Calcaterra, A., Cesario, A., Granone, P., Costa, R., Ciarlo, M., Alama, A., Russo, P., Targeting alpha7-nicotinic receptor for the treatment of pleural mesothelioma., <>, 2008; (Ottobre): 2296-2311 [http://hdl.handle.net/10807/5462]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/5462
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