dextromethorphan and Carcinogenesis

Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Carcinogenesis; Cell Line, Tumor; Dextromethorphan; DNA Methylation; Drug Repositioning; Electronic Nicotine Delivery Systems; Esophageal Squamous Cell Carcinoma; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Janus Kinase 2; Male; Metformin; Mice; Nicotine; SOXB1 Transcription Factors; STAT3 Transcription Factor