Prevention of Pancreatic Cancer by the Beta-blocker Propranolol

Overview

Journal Anticancer Drugs

Specialty Oncology

Date 2009 Apr 24

PMID 19387337

Citations 54

Authors

Hussein A Al-Wadei

Mohammed H Al-Wadei

Hildegard M Schuller

Affiliations

Soon will be listed here.

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 (beta-ARs) stimulate the proliferation and migration of human PDAC cells in vitro by cAMP-dependent signaling and that the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) activates this pathway directly in vitro while additionally stimulating the release of noradrenaline/adrenaline by binding to alpha7 nicotinic acetylcholine receptors (alpha7 nAChR) in hamsters. In this study, we have tested the hypothesis that the beta-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 alpha7 nAChR associated with significant inductions of p-CREB, p-ERK1/2, and increases in epidermal growth factor and vascular endothelial growth factor 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 epidermal growth factor, and PKA-dependent release of vascular endothelial growth factor while additionally downregulating the alpha7 nAChR by inhibiting 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.

Citing Articles

Pancreatic Cancer: A Review of Risk Factors.

Grigorescu R, Husar-Sburlan I, Gheorghe C Life (Basel). 2024; 14(8).

PMID: 39202722 PMC: 11355429. DOI: 10.3390/life14080980.

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts.

Koltai T, Fliegel L Pharmaceuticals (Basel). 2024; 17(6).

PMID: 38931411 PMC: 11206832. DOI: 10.3390/ph17060744.

The Crosstalk between Nerves and Cancer-A Poorly Understood Phenomenon and New Possibilities.

Benzaquen D, Lawrence Y, Taussky D, Zwahlen D, Oehler C, Champion A Cancers (Basel). 2024; 16(10).

PMID: 38791953 PMC: 11120349. DOI: 10.3390/cancers16101875.

Neuropancreatology: The Nervous System and Pain Management in Pancreatic Diseases.

Nicoletti A, Vitale F, Paratore M, Quero G, Negri M, Nista E Life (Basel). 2024; 14(3).

PMID: 38541624 PMC: 10970869. DOI: 10.3390/life14030299.

Current trends and future prospects of drug repositioning in gastrointestinal oncology.

Fatemi N, Karimpour M, Bahrami H, Zali M, Chaleshi V, Riccio A Front Pharmacol. 2024; 14:1329244.

PMID: 38239190 PMC: 10794567. DOI: 10.3389/fphar.2023.1329244.

References

Wong H, Yu L, Lam E, Tai E, Wu W, Cho C . Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells. Toxicol Appl Pharmacol. 2007; 221(3):261-7. DOI: 10.1016/j.taap.2007.04.002. View

Mancuso A, Calabro F, Sternberg C . Current therapies and advances in the treatment of pancreatic cancer. Crit Rev Oncol Hematol. 2006; 58(3):231-41. DOI: 10.1016/j.critrevonc.2006.02.004. View

Schuller H, Tithof P, Williams M, Plummer 3rd H . The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptor-mediated release of arachidonic acid. Cancer Res. 1999; 59(18):4510-5. View

Wanamaker C, Christianson J, Green W . Regulation of nicotinic acetylcholine receptor assembly. Ann N Y Acad Sci. 2003; 998:66-80. DOI: 10.1196/annals.1254.009. View

Hruban R, Fukushima N . Pancreatic adenocarcinoma: update on the surgical pathology of carcinomas of ductal origin and PanINs. Mod Pathol. 2007; 20 Suppl 1:S61-70. DOI: 10.1038/modpathol.3800685. View

Shin V, Wu W, Chu K, Koo M, Wong H, Lam E . Functional role of beta-adrenergic receptors in the mitogenic action of nicotine on gastric cancer cells. Toxicol Sci. 2006; 96(1):21-9. DOI: 10.1093/toxsci/kfl118. View

Schuller H, Zhang L, Weddle D, Castonguay A, Walker K, Miller M . The cyclooxygenase inhibitor ibuprofen and the FLAP inhibitor MK886 inhibit pancreatic carcinogenesis induced in hamsters by transplacental exposure to ethanol and the tobacco carcinogen NNK. J Cancer Res Clin Oncol. 2002; 128(10):525-32. DOI: 10.1007/s00432-002-0365-y. View

Weddle D, Tithoff P, Williams M, Schuller H . Beta-adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas. Carcinogenesis. 2001; 22(3):473-9. DOI: 10.1093/carcin/22.3.473. View

Al-Wadei H, Schuller H . beta-Carotene promotes the development of NNK-induced small airway-derived lung adenocarcinoma. Eur J Cancer. 2009; 45(7):1257-1264. PMC: 2694439. DOI: 10.1016/j.ejca.2008.10.035. View

10.

Schuller H . Neurotransmission and cancer: implications for prevention and therapy. Anticancer Drugs. 2008; 19(7):655-71. DOI: 10.1097/CAD.0b013e3283025b58. View

11.

Wu W, Wong H, Luo S, Chan K, Huang F, Hui M . 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors. Cancer Res. 2005; 65(12):5272-7. DOI: 10.1158/0008-5472.CAN-05-0205. View

12.

Jin Z, Gao F, Flagg T, Deng X . Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation. J Biol Chem. 2004; 279(38):40209-19. DOI: 10.1074/jbc.M404056200. View

13.

Cekanova M, Majidy M, Masi T, Al-Wadei H, Schuller H . Overexpressed Raf-1 and phosphorylated cyclic adenosine 3'-5'-monophosphatate response element-binding protein are early markers for lung adenocarcinoma. Cancer. 2007; 109(6):1164-73. DOI: 10.1002/cncr.22520. View

14.

Askari M, Tsao M, Schuller H . The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through beta-adrenergic transactivation of EGF receptors. J Cancer Res Clin Oncol. 2005; 131(10):639-48. DOI: 10.1007/s00432-005-0002-7. View

15.

Grau M, Soley M, Ramirez I . Interaction between adrenaline and epidermal growth factor in the control of liver glycogenolysis in mouse. Endocrinology. 1997; 138(6):2601-9. DOI: 10.1210/endo.138.6.5183. View

16.

Laag E, Majidi M, Cekanova M, Masi T, Takahashi T, Schuller H . NNK activates ERK1/2 and CREB/ATF-1 via beta-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells. Int J Cancer. 2006; 119(7):1547-52. DOI: 10.1002/ijc.21987. View

17.

Barik J, Wonnacott S . Indirect modulation by alpha7 nicotinic acetylcholine receptors of noradrenaline release in rat hippocampal slices: interaction with glutamate and GABA systems and effect of nicotine withdrawal. Mol Pharmacol. 2005; 69(2):618-28. DOI: 10.1124/mol.105.018184. View

18.

Sood A, Bhatty R, Kamat A, Landen C, Han L, Thaker P . Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res. 2006; 12(2):369-75. PMC: 3141061. DOI: 10.1158/1078-0432.CCR-05-1698. View

19.

Schuller H, Jorquera R, Reichert A, Castonguay A . Transplacental induction of pancreas tumors in hamsters by ethanol and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res. 1993; 53(11):2498-501. View

20.

Schuller H . Is cancer triggered by altered signalling of nicotinic acetylcholine receptors?. Nat Rev Cancer. 2009; 9(3):195-205. DOI: 10.1038/nrc2590. View