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

Alama A, Bruzzo C, Cavalieri Z, Forlani A, Utkin Y, Casciano I, Romani M - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Unit, Istituto Nazionale per la Ricerca sul Cancro, IST, Genova, Italy.

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.

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Raw IVIS determination of tumor growth in mice treated with α-cobratoxin according to schedules 1 and 2.X denotes the dead animals.
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pone-0020695-g009: Raw IVIS determination of tumor growth in mice treated with α-cobratoxin according to schedules 1 and 2.X denotes the dead animals.

Mentions: The same treatment schedules were also utilized with the α-cobratoxin. The results of this set of experiments showed that this toxin lacks evident antitumoral activity as well. In Figure 9, we report the raw IVIS determination for each mice treated with α-cobratoxin according to schedules 1 and 2 while in Figure 8, Panel C, we show the average fold-change of emission in the control and treated mice. As can be seen, the treatment does not appreciably influence tumor growth as photon emission in treated mice was comparable to that of the controls at each time-point. The number of animals that had to be sacrificed for humanitarian reasons before the end of the observational period was higher in control as compared to treated mice. However, it must be pointed out that also in this case all animals, at day 28, presented massive tumor growth that extended outside the thoracic cavity irrespectively of the treatment plan.


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

Alama A, Bruzzo C, Cavalieri Z, Forlani A, Utkin Y, Casciano I, Romani M - PLoS ONE (2011)

Raw IVIS determination of tumor growth in mice treated with α-cobratoxin according to schedules 1 and 2.X denotes the dead animals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3113800&req=5

pone-0020695-g009: Raw IVIS determination of tumor growth in mice treated with α-cobratoxin according to schedules 1 and 2.X denotes the dead animals.
Mentions: The same treatment schedules were also utilized with the α-cobratoxin. The results of this set of experiments showed that this toxin lacks evident antitumoral activity as well. In Figure 9, we report the raw IVIS determination for each mice treated with α-cobratoxin according to schedules 1 and 2 while in Figure 8, Panel C, we show the average fold-change of emission in the control and treated mice. As can be seen, the treatment does not appreciably influence tumor growth as photon emission in treated mice was comparable to that of the controls at each time-point. The number of animals that had to be sacrificed for humanitarian reasons before the end of the observational period was higher in control as compared to treated mice. However, it must be pointed out that also in this case all animals, at day 28, presented massive tumor growth that extended outside the thoracic cavity irrespectively of the treatment plan.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Unit, Istituto Nazionale per la Ricerca sul Cancro, IST, Genova, Italy.

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.

Show MeSH
Related in: MedlinePlus