Pathways of Resistance: Potential Effects of Nicotine on Cancer and Treatment Response

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

Tobacco use is the most significant preventable cause of cancer and continued tobacco use during cancer treatment is associated with poor outcome. Cessation strategies commonly use nicotine to address the physical tobacco addiction during chemotherapy and radiotherapy; however, the effects of nicotine on cancer and treatment outcome are not well established.

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Materials/Methods 

Extensive literature search using PubMed on nicotine and cancer were used to assess the effects of nicotine on tumor promotion and progression. Signal transduction pathway activation and functional outcomes were compiled and specific key modulators of signal transduction were identified. A protein interaction construct was generated delineating over 30 key modulators and greater than 100 interactions of the effects of nicotine on signal transduction affecting tumor outcome.

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Results 

Nicotine administration results in activation of multiple signal transduction pathways leading to increased tumor growth, angiogenesis, migration, invasion, and inhibition of apoptosis. Many effects of tobacco smoke on cancer promotion including growth and angiogenesis are modulated through nicotinic pathways. Nicotine signal transduction can occur through not only nicotinic acetylcholine receptors (nAChR), but also through beta adrenergic signals leading to the activation of multiple oncogenic pathways including PI3K, Akt, Ras, MEK, ERK1/2, MAPK, NF-kB, c-Src, AP-1, and COX resulting in tumor promotion. Through these and other pathways, nicotine induces production of growth factors including epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). Since nicotine activates several parallel oncogenic and tumor promoting pathways, nicotine has the potential not only to promote tumor growth, but also to reduce the effects of chemotherapy and specific molecular inhibitors. As a consequence, the apoptotic effects of chemotherapeutics including cisplatin, gemcitabine, staurosporine, taxol, and etoposide are prevented with the administration of nicotine.

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Conclusions 

This construct generates many hypotheses for examining the role of nicotine in tumor promotion and progression. Furthermore, nicotine administration appears to impair cancer cell response to standard non-surgical cancer treatment regimens. These results have strong implications for abstaining from tobacco use as well as nicotine exposure during cancer treatment.