Targeting α7-nicotinic receptor for the treatment of pleural mesothelioma

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 α-Cobratoxin (α-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 α7-nAChR expression and their growth was significantly inhibited by α-CbT. Severe induction of apoptosis was observed after exposure to α-CbT [IC80-90]. 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 α-CbT acute LD50 was 0.15 mg/kg. The LD100 [0.24 mg/kg] induced fatal respiratory failure and massive kidney necrosis. Phase II experiments with 0.12 ng/kg α-CbT (1/1000 of LD10) 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 α-CbT. Non-immunogenic derivatives of the α-CbT molecule need to be developed for possible human use.