Journal
EUROPEAN JOURNAL OF CANCER
Volume 44, Issue 15, Pages 2296-2311Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2008.06.045
Keywords
alpha 7-Nicotinic receptor; Mesothelioma; Apoptosis; Survivin; Antitumour activity
Categories
Funding
- Paola Giancola per la Ricerca sul Cancro
- Associazione Italiana per la Ricerca sul Cancro (Comitato Ligure) Milan Italy
Ask authors/readers for more resources
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 xeno-transplanted NOD/SCID mice. Cells showed alpha 7-nAChR expression and their growth was significantly inhibited by alpha-CbT. Severe induction of apoptosis was observed after exposure to alpha-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 alpha-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 alpha-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 alpha-CbT. Non-immunogenic derivatives of the alpha-CbT molecule need to be developed for possible human use. (C) 2008 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available