Retracted: Inhibition of non‐neuronal α7‐nicotinic receptor reduces tumorigenicity in A549 NSCLC xenografts

Abstract

Nicotinic acetylcholine receptors (nAChR) are expressed on bronchial epithelial and non-small cell lung cancer cells and are involved in cell growth regulation. Nicotine (classical nAChR agonist) induced cell proliferation, whereas nAChR antagonists, dtubocurarine or a-cobratoxin (a-CbT), induced cell death. In the current study, we further explored the antitumor potential mechanisms and activities of a-CbT. NOD/SCID mice were grafted intraperitoneally or orthotopically and treated with a-CbT. a-CbT treatment [0.04 ng/kg or 0.12 ng/kg] induced a strong reduction in tumor size (90%) in comparison with mice treated with the vehicle alone. Tumor inhibition was related to severe induction of apoptosis. Moreover, neoangiogenesis was strongly inhibited (reduction of cells positive to vascular endothelial growth factor and CD31). Biochemical analyses of the cells, isolated by the primary lung tumor in a-CbT-treated mice, showed apoptosis features characterized by: (i) inhibition of BAD phosphorylation at Ser 112 and Ser 136; (ii) BAD dissociation from 14-3-3; (iii) BAD association with BCL-XL; and (iv) cleavage of caspase-9. Moreover, these cells were unable to grow in soft agar and develop tumor, when reinjected into mice. The small interfering RNA-mediated silencing of the a7-nAChR gene confirmed that a-CbT specifically inhibited the a7-nAChR-mediated survival pathway in A549 cells. Furthermore, the specificity of a-CbT is reinforced by the lack of effect of short chain toxin (Erabutoxin-a). Once more, the no effect of the low-affinity R33E-modified a-CbT strengthened the specificity of this inhibition. Although a7-nAChR antagonists, such as a-CbT, are unlikely to be a primary therapy, it may provide lead compounds for the design of clinically useful drugs. ' UICCKey words: nicotinic acetylcholine receptors; cobratoxin; mouse model lung cancer; tumor-induced apoptosis; neoangiogenesis inhibition Lung cancer is the leading cause of cancer mortality worldwide. Epidemiologic studies have demonstrated that cigarette smoking is the major risk factor in its development, with a striking doseresponse relationship. It is estimated that 80-90% of lung cancer incidence can be attributed to cigarette smoking.1 Despite years of research, the prognosis for patients with lung cancer remains dismal, with a 5-year survival rate of 14%. Currently, the usual chemotherapy regimen (adjuvant or neoadjuvant) combines a platinum-containing drug with another cytotoxic agent (i.e., gemcitabin, Taxol or navelbine). However, platinum-based therapies have drawbacks: severe toxic effects for the patient and drug resistance in the tumor cells.2 Future directions for treatment are heavily weighted toward targeted therapies, namely those aimed at molecular abnormalities involved in the pathogenesis of lung cancer 3 rather than traditional cytotoxic agents. 4 Currently, it has been established that acetylcholine (ACh) is widely synthesized by a variety of non-neuronal cell types, including airway epithelial cells. [5][6][7][8][9][10][11][12][13][14...

Influenza Virus Infection Aggravates Stroke Outcome

“…21 This receptor is expressed by alveolar macrophages and epithelial cells in the respiratory tract, which are the main sources of cytokine production in influenza. 20,21 Our study demonstrates that activation of ␣7nAchR by the selective agonist GTS-21 inhibited the release of RANTES from influenza virus-infected lung epithelial cells. On GTS-21 treatment, lower levels of circulating RANTES were associated with decreased levels of inflammatory mediators in the brain and smaller infarct size.…”

“…19 Both cell types express the ␣7 nicotinic acetylcholine receptor (␣7nAchR) that limits cytokine release in the reflex control of immunity. 20,21 Therefore, we investigated whether the ␣7nAchR agonist GTS-21 interferes with the effects of influenza virus infection. GTS-21 increased the viability of A549 lung epithelial cells infected by influenza virus ( Figure 6A) but had no effect on viral replication (data not shown).…”

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

“…33 Inhibition of CHRNA7 can reduce the tumorigenicity of lung cancer cells. 34 It is well accepted now that CHRNA7 is a valuable molecular target for therapy of lung cancer and its antagonists (eg, D-tubocurarine or a-CbT) might provide 'efficacious adjuvant therapy' for lung cancer. 25 Therefore, on the fact of that the CNV-3956 caused a different CHRNA7 expression, it should be in consideration for future individual's treatment.…”

α7 nicotinic acetylcholine receptors in lung cancer (Review)

“…Notably, a number of α7nAChRs antagonists have been investigated to explore its influence on tumor progression (56,57,(64)(65)(66)69). Provided that α7nAChR is a major genetic biomarker of nAChRs for lung cancer (70), strategies that target α7nAChR may be useful in the treatment of lung cancer for therapeutic purposes.…”