Nicotinic-nAChR signaling mediates drug resistance in lung cancer

Cheng, Wanli; Chen, Kuan Yuan; Lee, Kang Yun; Feng, Po Hao; Wu, Sheng

doi:10.7150/jca.36359

“…The non-neuronal cholinergic system contributes to the regulation of cell functions such as cell-cell interaction, apoptosis, and proliferation and it is well established that human bronchial epithelial cells contain nAChRs. The airway epithelium expresses α3, α4, α5, α7, α9, β2, and β4-nAChRs subunits [34][35][36][37] and their contribution has been discussed in the framework of airway epithelial basal cell proliferationdifferentiation and their alteration in lung cancers [38]. These nAChRs are mentioned here as possible targets of Covid-19 infection of the lung, which would take place concomitantly with, and/or as a consequence of, the neuro-infection.…”

mentioning

confidence: 99%

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

Changeux¹,

Amoura²,

Rey³

et al. 2020

Comptes Rendus. Biologies

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Background: Ivermectin is a widely used antiparasitic drug with known e cacy against several single-strain RNA viruses. Recent data shows signi cant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. Methods: An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology pro le including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic pro le of ivermectin in plasma and lungs was determined in all animals. Results: There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 grams/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean C max 86.2 ng/ml vs 26.2 ng/ml in the lower dose group and 152 ng/ml vs 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for lowdose females. Conclusion: nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.

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“…T he airway epithelium expresses 3, 4, 5, 7, 9, 2, and 4-nAChRs subunits [34][35][36][37] and their contribution has been discussed in the framework of airway epithelial basal cell proliferation-differentiation and their alteration in lung cancers [38].…”

mentioning

confidence: 99%

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

Changeux¹,

Amoura

²

,

Rey

³

et al. 2020

Preprint

View full text Add to dashboard Cite

SARS-CoV-2 epidemics raises a considerable issue of public health at the planetary scale. T here is a pressing urgency to find treatments based upon currently available scientific knowledge. T herefore, we tentatively propose a hypothesis which hopefully might ultimately help saving lives. Based on the current scientific literature and on new epidemiological data which reveal that current smoking status appears to be a protective factor against the infection by SARS-CoV-2 [1], we hypothesize that the nicotinic acetylcholine receptor (nAChR) plays a key role in the pathophysiology of Covid-19 infection and might represent a target for the prevention and control of Covid-19 infection. Symptomatic Covid-19 disease (as caused by SARS-CoV-2 virus) is observed in 2.5 percent of infected individuals [2] indicating an individual variability in the clinical presentation. Among the epidemiological and clinical features of Covid-19, the following features are of special interest for understanding the patho-physiolology, namely: (1) in outpatients with favorable outcome : neurological/psychiatric disorders, especially loss of sense of smell which is specific of the disease and (2) in hospitalized older patients with a poor prognosis : systemic hyperinflammatory syndrome with increased levels of circulating cytokines and atypical acute respiratory distress syndrome with loss of neurological control of lung perfusion regulation and hypoxic vasoconstriction [3]. T his raises the issue of the basis of inter-individual variability for the susceptibility to infection.T he nAChR appears as a hypothetical clue for the main clinical manifestations of Covid-19. It is accepted that the angiotensin converting enzyme 2 (ACE2), represents the principal receptor molecule for SARS- . ACE2 is expressed at the transcriptomic level in the lung, the small intestine and colon, in the kidney, in the testis, in the heart muscle and in the brain, yet the protein is not detected in the lung [7]. In the brain, ACE2 is expressed in both neurons and glia and particularly present in the brain

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“…T he airway epithelium expresses 3, 4, 5, 7, 9, 2, and 4-nAChRs subunits [34][35][36][37] and their contribution has been discussed in the framework of airway epithelial basal cell proliferation-differentiation and their alteration in lung cancers [38].…”

mentioning

confidence: 99%

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

Changeux¹,

Amoura

²

,

Rey

³

et al. 2020

Preprint

View full text Add to dashboard Cite

SARS-CoV-2 epidemics raises a considerable issue of public health at the planetary scale. T here is a pressing urgency to find treatments based upon currently available scientific knowledge. T herefore, we tentatively propose a hypothesis which hopefully might ultimately help saving lives. Based on the current scientific literature and on new epidemiological data which reveal that current smoking status appears to be a protective factor against the infection by SARS-CoV-2 [1], we hypothesize that the nicotinic acetylcholine receptor (nAChR) plays a key role in the pathophysiology of Covid-19 infection and might represent a target for the prevention and control of Covid-19 infection.

show abstract

Nicotinic-nAChR signaling mediates drug resistance in lung cancer

Cited by 34 publications

References 209 publications

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

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