Inhibition of the nicotinic acetylcholine receptors by cobra venom α-neurotoxins: is there a perspective in lung cancer treatment?

Abstract

Nicotine exerts its oncogenic effects through the binding to nicotinic acetylcholine receptors (nAChRs) and the activation of downstream pathways that block apoptosis and promote neo-angiogenesis. The nAChRs of the α7 subtype are present on a wide variety of cancer cells and their inhibition by cobra venom neurotoxins has been proposed in several articles and reviews as a potential innovative lung cancer therapy. However, since part of the published results was recently retracted, we believe that the antitumoral activity of cobra venom neurotoxins needs to be independently re-evaluated.We determined the activity of α-neurotoxins from Naja atra (short-chain neurotoxin, α-cobrotoxin) and Naja kaouthia (long-chain neurotoxin, α-cobratoxin) in vitro by cytotoxicity measurements in 5 lung cancer cell lines, by colony formation assay with α7nAChRs expressing and non-expressing cell lines and in vivo by assessing tumor growth in an orthotopic Non-Obese Diabetic/Severe Combined Immunodeficient (NOD/SCID) mouse model system utilizing different treatment schedules and dosages.No statistically significant reduction in tumor growth was observed in the treatment arms in comparison to the control for both toxins. Paradoxically α-cobrotoxin from Naja atra showed the tendency to enhance tumor growth although, even in this case, the statistical significance was not reached.In conclusion our results show that, in contrast with other reports, the nAChR inhibitors α-cobratoxin from N. kaouthia and α-cobrotoxin from N. atra neither suppressed tumor growth nor prolonged the survival of the treated animals.

• Authors: Angela Alama, Cristina Bruzzo, Zita Cavalieri, Alessandra Forlani, Yuri Utkin, Ida Casciano, Massimo Romani
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e20695 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21695184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chrna7 protein, human
• Chrna7 protein, mouse
• Cobra Neurotoxin Proteins
• Elapid Venoms
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• alpha-cobratoxin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Clone Cells
• Cobra Neurotoxin Proteins (toxicity)
• Drug Screening Assays, Antitumor
• Elapid Venoms (toxicity)
• Humans
• Luminescent Measurements
• Lung Neoplasms (drug therapy)
• Mice
• Receptors, Nicotinic (metabolism)
• Toxicity Tests
• alpha7 Nicotinic Acetylcholine Receptor