Prevention of pancreatic cancer by the beta-blocker propranolol

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer deaths and is unresponsive to existing therapy. Smoking and alcohol-induced pancreatitis are among the risk factors for PDAC. We have previously reported that beta-adrenergic receptors (β-ARs) stimulate the proliferation and migration of human PDAC cells in vitro via cAMP-dependent signaling and that the nicotine-derived nitrosamine NNK activates this pathway directly in vitro while additionally stimulating the release of noradrenaline/adrenaline by binding to α7 nicotinic acetylcholine receptors in hamsters. In the current study, we have tested the hypothesis that the β-AR antagonist propranolol prevents the development of PDAC induced in hamsters with ethanol-induced pancreatitis by NNK. We found that propranolol had strong cancer preventive effects in this animal model. Western blots of pancreatic duct cells and PDAC cells harvested by laser capture microscopy showed significant upregulation of the α7nicotinic acetylcholine receptor (α7nAChR) associated with significant inductions of p-CREB, p-ERK1/2 and increases in EGF and VEGF in PDAC cells of hamsters not treated with propranolol. These effects were reversed by treatment with propranolol. Our data suggest that propranolol may prevent the development of PDAC by blocking cAMP-dependent intracellular signaling, cAMP-dependent release of EGF and PKA-dependent release of VEGF while additionally downregulating the α7nAChR via inhibition of cAMP-mediated subunit assembly. We conclude that increased cAMP signaling is an important factor that drives the development and progression of PDAC and that the inhibition of cAMP formation is a promising new target for the prevention and adjuvant therapy of PDAC.

Neural plasticity in pancreatitis and pancreatic cancer

“…[91][92][93][94][95][96] Indeed, several studies showed the beneficial effects of administering propanolol as an unselective β-blocker with reduced pancreatic cancer incidence in hamsters with ethanol-induced pancreatitis. 97 At the cellular level, β-adrenergic receptors were shown to stimulate the proliferation and migration of human pancreatic cancer cells by cAMP-dependent signalling. 97 Pancreatic cancer cells are known to upregulate the α7 nicotinic acetyl choline receptor, and this upregulation is associated with induction of phosphorylated cyclic AMP-responsive element-binding protein (p-CREB), phosphorylated extracellular regulated kinase 1/2 (p-ERK1/2; also known as mitogen activated protein kinase 3/1), and epidermal growth factor and vascular endothelial growth factor in pancreatic cancer cells.…”

“…97 At the cellular level, β-adrenergic receptors were shown to stimulate the proliferation and migration of human pancreatic cancer cells by cAMP-dependent signalling. 97 Pancreatic cancer cells are known to upregulate the α7 nicotinic acetyl choline receptor, and this upregulation is associated with induction of phosphorylated cyclic AMP-responsive element-binding protein (p-CREB), phosphorylated extracellular regulated kinase 1/2 (p-ERK1/2; also known as mitogen activated protein kinase 3/1), and epidermal growth factor and vascular endothelial growth factor in pancreatic cancer cells. 97 Considering the increasing number of studies 98-100 that reported the tumorigenic effects of sympathetic nervous system activation, 101 targeting the sympathetic nervous system in cancers seems to hold promise as a potential future adjunct therapy option.…”

Proliferation of the human urothelium is induced by atypical β1‐adrenoceptors

“…During the last years, several studies have reported that autonomic receptors may regulate tumour proliferation and invasion. Previous reports have demonstrated that b-adrenoceptors may contribute substantially to proliferation of different tumours including pancreatic and vascular tumours and melanoma (Al-Wadei et al, 2009;Chisholm et al, 2012;Dal Monte et al, 2013). b-adrenoceptors have also been suggested to constitute the link between chronic stress and the development of acute lymphoblastic leukaemia (ALL) and pancreatic cancer (Lamkin et al, 2012;Kim-Fuchs et al, 2014).…”

The Role of Common Pharmaceutical Agents on the Prevention and Treatment of Pancreatic Cancer

“…With regards to pancreas cancer, β-adrenergic agonists stimulate human ductal adenocarcinoma cell growth via adenyl cyclase, which has downstream effects on cAMP, protein kinase A (PKA), and phosphorylation of cyclic AMP response element binding protein (p-CREB) 54,59. PKA also activates the EGFR pathway.…”

“…PKA also activates the EGFR pathway. Furthermore, tobacco, via the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), may also stimulate pancreatic cell growth via this same β-adrenergic mechanism 54,60. In an animal model of hamsters with ethanol-induced pancreatitis, the nonselective β-blocker propranalol showed strong antineoplastic effect, inhibiting upregulation of the α7 nicotinic acetylcholine receptor (α7nAChR) as well the extracellular signal regulated protein kinases (ERK1/2), p-CREB, EGF, and vascular endothelial growth factor 54…”