A recent study published in Nature reports that metformin and dextromethorphan, two drugs already in use to treat other diseases, were found to decrease the occurrence of nicotine-induced cancer and could be repurposed as a cancer treatment.
Smoking is the most impactful lifestyle-related risk factor in many different cancer types, including oesophageal squamous cell carcinoma (ESCC). As a major component of tobacco and e-cigarettes, nicotine is responsible for both addiction to smoking and is also a carcinogen.
The carcinogenic effects of nicotine and their underlying molecular mechanisms are not well understood. As a result, there is a lack of effective therapeutic agents to block its detrimental effects.
Mechanism of Action
Nicotine exerts its biological effects mainly via nicotinic acetylcholine receptors (NAChRs), which are composed of multiple subunits. The subunits CHRNA7 and CHRNA9 have been reported to be capable of inducing cancer progression. Therefore, targeting these subunits could inhibit nicotine induced tumour initiation.
This study provided experimental evidence that nicotine enhances the malignancy and tumour initiating capacity of ESCC through CHRNA7. Through interactions with CHRNA7, nicotine subsequently activates the JAK2/STAT3/SOX2 signalling pathway. Several components of this pathway have known associations with cancer development.
Furthermore, patients with high CHRNA7 were found to have significantly shorter overall survival. Cox regression analyses also indicated that CHRNA7 can act as an independent prognostic factor for ESCC patients.
The group explored whether inhibiting the expression of CHRNA7 or repressing its activity could prove to be an efficacious therapeutic strategy. In multiple mouse models, dextromethorphan and metformin synergistically repressed the nicotine-enhanced initiation of cancer, and inhibited its progression. These findings were further supported by patient sample analysis, bioinformatic analyses and cellular studies.
Mechanistically, dextromethorphan non-competitively inhibits nicotine binding to CHRNA7. On the other hand, metformin down regulates CHRNA7 expression by antagonising the nicotine-induced promoter DNA hypomethylation of CHRNA7. Metformin may also be able to effectively hypermethylate CHRNA7 in breast, endometrial and ovarian cancer cells.
The findings of this study support the prognostic and therapeutic importance of CHRNA7 in nicotine-induced cancer. Since metformin and dextromethorphan are both clinically approved drugs with minimal side effects, the combination of these drugs has a high potential as either a preventative or therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.
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