Targeting alpha7-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 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
Alessia
A
Lung Cancer Unit, National Cancer Research Institute, 16032 Genoa, Italy.
Paleari
Laura
L
Servent
Denis
D
Sessa
Fausto
F
Dominioni
Lorenzo
L
Ognio
Emanuela
E
Cilli
Michele
M
Vacca
Paola
P
Mingari
Mariacristina
M
Gaudino
Giovanni
G
Bertino
Pietro
P
Paolucci
Massimo
M
Calcaterra
Andrea
A
Cesario
Alfredo
A
Granone
Pierluigi
P
Costa
Roberta
R
Ciarlo
Monica
M
Alama
Angela
A
Russo
Patrizia
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D003039:Cobra Neurotoxin Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D018733:Nicotinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000970:Antineoplastic Agents; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D003039:Cobra Neurotoxin Proteins; D009363:Neoplasm Proteins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C025154:alpha-cobratoxin