Effects of tobacco constituents and psychological stress on the beta-adrenergic regulation of non-small cell lung cancer and pancreatic cancer: Implications for intervention

Abstract

This review summarizes current preclinical and clinical evidence in support of the hypothesis that smoking and psychological stress have significant cancer promoting effects on non small cell lung cancer and pancreatic cancer via direct and indirect effects on nicotinic receptor-regulated beta-adrenergic signaling. Evidence is provided that targeted pharmacological interference with the resulting hyperactive cAMP-dependent signaling by beta-blockers or by γ-aminobutyric acid as well as positive psychological influences may be highly effective in preventing and improving clinical outcomes of these cancers, provided that appropriate diagnostic protocols are followed to monitor systemic levels of stress neurotransmitters and cAMP.

Regulation of nonsmall‐cell lung cancer stem cell like cells by neurotransmitters and opioid peptides

“…In accord with these preclinical findings, some investigations have described improved clinical outcomes in such cancer patients who received incidental beta‐blocker therapy . However, pending on the type, dose and duration of beta‐blocker treatment used, this class of agents may have tumor promoting effects due to reactive desensitization of beta‐adrenergic receptors in response to general beta‐blockers or upregulation of beta‐2 adrenergic receptors in response to beta‐1 blockade . In addition, cAMP‐driven pathways can be activated by a host of environmental and lifestyle factors independent of beta‐adrenergic receptors, including exposure to estrogen, corticosteroids, beta‐carotene as well as phosphodiesterase inhibitors, including caffeine and theophylline .…”

“…28,[44][45][46] However, pending on the type, dose and duration of beta-blocker treatment used, this class of agents may have tumor promoting effects due to reactive desensitization of beta-adrenergic receptors in response to general beta-blockers or upregulation of beta-2 adrenergic receptors in response to beta-1 blockade. 47 In addition, cAMP-driven pathways can be activated by a host of environmental and lifestyle factors independent of beta-adrenergic receptors, including exposure to estrogen, 14 corticosteroids, 48 beta-carotene 49,50 as well as phosphodiesterase inhibitors, including caffeine 51 and theophylline. 52 In addition, numerous over-the counter decongestants as well as prescription broncho-dilators increase cAMP levels via epinephrine-like effects on adrenergic receptors.…”

A new twist to neurotransmitter receptors and cancer

“…In addition to IGF-2, β-AR-I agonists also induced the release of AA, EGF, VEGF, interleukin-6 as well as several cancer stem cell markers. [36,[64][65][66] In turn, these effects can be caused by elevated systemic levels of stress neurotransmitters in response to stress or tobacco exposure, by direct binding of NNK in tobacco products to β-ARs, or by medications that are beta-adrenergic agonists. In addition, epithelial cancer cells and their respective cancer stem cells synthesize and release their own Epi and Nor upon activation of nAChRs by nicotine or nicotine-derived nitrosamines.…”

“…[33,36] The proposed repurposing of beta-blockers and Ca 2+ -channel blockers for lung cancer prevention would therefore inhibit There is an ongoing international discussion on the potential usefulness of beta-blockers for cancer intervention, with numerous preclinical studies reporting significant cancer inhibition whereas clinical investigations have generated controversial data with some even reporting cancer promoting effects. [28,29,64,[67][68][69][70][71] The potential usefulness of beta-blockers for adjuvant cancer treatment has additionally been discussed in depth based by comprehensive reviews of published preclinical and clinical literature. [67,72,73] By contrast, the current review analyzes mechanistic aspects of G s -coupled receptors and their physiological inhibitors and their modulating effects on cancer.…”

Autophagy-Related Gene Expression Changes Are Found in Pancreatic Cancer and Neurodegenerative Diseases

“…The role of neurology genes in the progression and metastasis of cancer in general has been emphasized recently. In many reviews, Hildegard M. Schuller established the theory that modulation of the autonomic nervous system is responsible for driving cancer development, progression, and resistance to chemotherapy not only in non-small-cell lung cancer and pancreatic ductal adenocarcinoma but also in other cancers [43][44][45][46][47][48].…”