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http://dx.doi.org/10.7314/APJCP.2014.15.22.9567

Are Beta Blockers New Potential Anticancer Agents?  

Akbar, Shahid (Department of Pharmacology, College of Pharmacy, Qassim University)
Alsharidah, Mansour Saleh (Department of Physiology, College of Medicine, Qassim University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.15, no.22, 2014 , pp. 9567-9574 More about this Journal
Abstract
${\beta}$-Blockers have been one of the most widely used and versatile drugs for the past half a century. A new potential for their use as anti-cancer drugs has emerged in the past few years. Various retrospective case control studies have been suggestive that use of ${\beta}$-blockers before the diagnosis of cancer could have preventive and protective effects against non-small cell lung carcinoma, melanoma, and breast, pancreatic and prostate cancers. Experimental and clinical observations are still inconclusive with some inconsistent findings. However, indications are pointing toward a positive role of some ${\beta}$-blockers against certain forms of cancers. This mini review is an effort to present the up to date published results of case-control studies and experimental findings.
Keywords
Beta; blockers; adrenoceptors; anticancer; breast; ovarian; pancreatic; prostate;
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1 Fitzgerald PJ (2009). Is norepinephrine an etiological factor in some types of cancer? Int J Cancer, 124, 257-63.   DOI
2 Fitzgerald PJ (2010). Testing whether drugs that weaken norepinephrine signaling prevent or treat various types of cancer. Clin Epidemiol, 2, 1-3.
3 Fryzek JP, Poulsen AH, Lipworth L, et al (2006). A cohort study of antihypertensive medication use and breast cancer among Danish women. Breast Cancer Res Treat, 97, 231-6.   DOI
4 Ganz PA, Habel LA, Weltzien EK, Caan BJ, Cole SW (2011). Examining the influence of beta blockers and ACE inhibitors on the risk for breast cancer recurrence: results from the LACE cohort. Breast Cancer Res Treat, 129, 549-56.   DOI
5 Glasner A, Avraham R, Rosenne E, et al (2010). Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a betaadrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol, 184, 2449-57.   DOI
6 Goldfarb Y, Ben-Eliyahu S (2006). Surgery as a risk factor for breast cancer recurrence and metastasis: mediating mechanisms and clinical prophylactic approaches. Breast Disease, 26, 99-114.
7 Goldstein MR, Mascitelli L (2011). Surgery and cancer promotion: are we trading beauty for cancer? QJM, 104, 811-5.   DOI
8 Grytli HH, Fagerland MW, Fossa SD, Tasken KA (2014). Association between use of $\beta$-blockers and prostate cancerspecific survival: A cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur Urol, 65, 635-41.   DOI
9 Kim MO, Na SI, Lee MY, Heo JS, Han HJ (2008). Epinephrine increases DNA synthesis via ERK1/2s through cAMP, Ca(2+)/PKC, and PI3K/Akt signaling pathways in mouse embryonic stem cells. J Cell Biochem, 104, 1407-20.   DOI
10 Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al (2008) Propranolol for severe hemangiomas of infancy. N Engl J Med, 358, 2649-51.   DOI   ScienceOn
11 Lee JW, Shahzad MM, Lin YG, et al (2009). Surgical stress promotes tumor growth in ovarian carcinoma. Clin Cancer Res, 15, 2695-702.   DOI   ScienceOn
12 Lemeshow S, Sorensen HT, Phillips G, et al (2011). $\beta$-Blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomarkers Prev, 20, 2273-9.   DOI
13 Li CI, Malone KE, Weiss NS, et al (2003). Relation between use of antihypertensive medications and risk of breast carcinoma among women ages 65-79 years. Cancer, 98, 1504-13.   DOI
14 Li P, Wu WK, Wong HP, et al (2009). Chloroform extract of cigarette smoke induces proliferation of human esophageal squamous-cell carcinoma cells: modulation by betaadrenoceptors. Drug Chem Toxicol, 32, 175-81.   DOI
15 Liao X, Che X, Zhao W, et al (2010a). The $\beta$-adrenoceptor antagonist, propranolol, induces human gastric cancer cell apoptosis and cell cycle arrest via inhibiting nuclear factor ${\kappa}B$ signaling. Oncol Rep, 24, 1669-76.
16 Liao X, Che X, Zhao W, et al (2010b). Effects of propranolol in combination with radiation on apoptosis and survival of gastric cancer cells in vitro. Radiat Oncol, 5, 98.   DOI
17 Perron L, Bairati I, Harel F, Meyer F (2004). Antihypertensive drug use and the risk of prostate cancer (Canada). Cancer Causes Control, 15, 535-41.   DOI
18 Pasquier E, Street J, Pouchy C, et al (2013). $\beta$-blockers increase response to chemotherapy via direct antitumour and antiangiogenic mechanisms in neuroblastoma. Br J Cancer, 108, 2485-94.   DOI
19 Perez Pinero C, Bruzzone A, Sarappa MG, Castillo LF, Luthy IA (2012). Involvement of $\alpha{2}$- and $\beta{2}$-adrenoceptors on breast cancer cell proliferation and tumour growth regulation. Br J Pharmacol, 166, 721-36.   DOI
20 Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, et al (2010). Beta-adrenergic receptors in cancer: therapeutic implications. Oncol Res, 19, 45-54.   DOI
21 Perrone MG, Notarnicola M, Caruso MG, Tutino V, Scilimati A (2008). Upregulation of beta3-adrenergic receptor mRNA in human colon cancer: a preliminary study. Oncology, 75, 224-9.   DOI
22 Plummer HK 3rd, Yu Q, Cakir Y, Schuller HM (2004). Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines. BMC Cancer, 4, 93.   DOI
23 Powe DG, Voss MJ, Zanker KS, et al (2010). Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget, 1, 628-38.
24 Quoc Luong KV, Nguyen LT (2012). The roles of betaadrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms. Cancer Manag Res, 4, 431-45.
25 Aydiner A, Ciftci R, Karabulut S, Kilic L (2013). Does betablocker therapy improve the survival of patients with metastatic non-small cell lung cancer? Asian Pac J Cancer Prev, 14, 6109-14.   DOI   ScienceOn
26 Algazi M, Plu-Bureau G, Flahault A, Dondon MG, Le MG (2004). Could treatments with beta- blockers be associated with a reduction in cancer risk? Rev Epidemiol Sante Publique, 52, 53-65 (in French).
27 Algazi M, Plu-Bureau G, Flahault A, Dondon MG, Le MG (2006). Is beta-blocker treatment associated with a decrease in the risk of cancer. Lett Drug Des Discov, 3, 653-61.   DOI
28 Al-Wadei HA, Al-Wadei MH, Schuller HM (2009). Prevention of pancreatic cancer by the beta-blocker propranolol. Anticancer Drugs, 20, 477-82.   DOI
29 Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K (2011). Beta-blocker and breast cancer mortality: a population- based study. J Clin Oncol, 29, 2635-44.   DOI
30 Ben-Eliyahu S, Shakhar G, Page GG, Stefanski V, Shakhar K (2000). Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors. Neuroimmunomodulation, 8, 154-64.   DOI   ScienceOn
31 Benish M, Bartal I, Goldfarb Y, et al (2008). Perioperative use of beta-blocker and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol, 15, 2042-52.   DOI
32 Heitz F, du Bois A, Harter P, et al (2013). AGO study group; NCIC-CTG study group; EORTC-GCG study group . Impact of beta blocker medication in patients with platinum sensitive recurrent ovarian cancer-a combined analysis of 2 prospective multicenter trials by the AGO Study Group, NCIC-CTG and EORTC-GCG. Gynecol Oncol, 129, 463-6.   DOI
33 Grytli HH, Fagerland MW, Fossa SD, Tasken KA, Haheim LL (2013). Use of $\beta$-blockers is associated with prostate cancerspecific survival in prostate cancer patients on androgen deprivation therapy. Prostate, 73, 250-60.   DOI
34 Guo K, Ma Q, Wang L, et al (2009). Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol. Oncol Rep, 22, 825-30.
35 Hasegawa H, Saiki I (2002). Psychosocial stress augments tumor development through beta-adrenergic activation in mice. Jpn J Cancer Res, 93, 729-35.   DOI
36 Herlenius E, Lagercrantz H (2001). Neurotransmitters and neuromodulators during early human development. Early Hum Dev, 65, 21-37.   DOI
37 Hicks BM, Murray LJ, Powe DG, Hughes CM, Cardwell CR (2013). $\beta$-Blocker usage and colorectal cancer mortality: a nested case-control study in the UK Clinical Practice Research Datalink cohort. Ann Oncol, 24, 3100-6.   DOI
38 Holmes MD, Chen WY (2012). Hiding in plain view: the potential for commonly used drugs to reduce breast cancer mortality. Breast Cancer Res, 14, 216.   DOI
39 Holmes MD, Hankinson SE, Feskanich D, Chen WY (2013). Beta blockers and angiotensin-converting enzyme inhibitors' purported benefit on breast cancer survival may be explained by aspirin use. Breast Cancer Res Treat, 139, 507-13.   DOI
40 Lindgren ME, Fagundes CP, Alfano CM, et al (2013). Betablockers may reduce intrusive thoughts in newly diagnosed cancer patients. Psychooncology, 22, 1889-94.   DOI
41 Liu X, Wu WK, Yu L, et al (2008). Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via beta-adrenoceptor-dependent transactivation of extracellular signal-regulated kinase/cyclooxygenase-2 pathway. J Cell Biochem, 105, 53-60.   DOI
42 Livingstone E, Hollestein LM, van Herk-Sukel MP, et al (2013). $\beta$-Blocker use and all-cause mortality of melanoma patients: results from a population-based Dutch cohort study. Eur J Cancer, 49, 3863-71.   DOI
43 Lutgendorf SK, Cole S, Costanzo E, et al (2003). Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res, 9, 4514-21.
44 Lutgendorf SK, DeGeest K, Dahmoush L, et al (2011). Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun, 25, 250-5.   DOI
45 Masur K, Niggemann B, Zanker KS, Entschladen F (2001). Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res, 61, 2866-9.
46 Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, et al (2011). Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol, 29, 2645-52.   DOI
47 Monami M, Filippi L, Ungar A, et al (2013). Further data on beta-blockers and cancer risk: observational study and meta-analysis of randomized clinical trials. Curr Med Res Opin, 29, 369-78.   DOI
48 Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A (2002). Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney and lung and melanoma. Cancer, 94, 2698-705.   DOI   ScienceOn
49 Rodriguez C, Jacobs EJ, Deka A, et al (2009). Use of bloodpressure- lowering medication and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Causes Control, 20, 671-9.   DOI
50 Ronquist G, Rodriguez LA, Ruigomez A, et al (2004). Association between captopril, other antihyper-tensive drugs and risk of prostate cancer. Prostate, 58, 50-6.   DOI
51 Schuller HM (2009). Is cancer triggered by altered signaling of nicotinic acetylcholine receptors? Nat Rev Cancer, 9, 195-205.   DOI   ScienceOn
52 Schuller HM (2010). Beta-adrenergic signaling, a novel target for cancer therapy? Oncotarget, 1, 466-9.
53 Schuller HM, Al-Wadei HA (2012). Beta-adrenergic signaling in the development and progression of pulmonary and pancreatic adenocarcinoma. Curr Cancer Ther Rev, 8, 116-27.   DOI
54 Schuller HM, Al-Wadei HA, Majidi M (2008). GABA B receptor is a novel drug target for pancreatic cancer. Cancer, 112, 767-78.   DOI   ScienceOn
55 Schuller HM, Orloff M (1998). Tobacco-specific carcinogenic nitrosamines. Ligands for nicotinic acetylcholine receptors in human lung cancer cells. Biochem Pharmacol, 55, 1377-84.   DOI   ScienceOn
56 Schuller HM, Porter B, Riechert A (2000). Beta-adrenergic modulation of NNK-induced lung carcinogenesis in hamsters. J Cancer Res Clin Oncol, 126, 624-30.   DOI
57 Weddle DL, Tithoff P, Williams M, Schuller HM (2001). Betaadrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas. Carcinogenesis, 22, 473-9.   DOI
58 Sorensen GV, Ganz PA, Cole SW, et al (2013). Use of $\beta$-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and risk of breast cancer recurrence: a Danish nationwide prospective cohort study. J Clin Oncol, 31, 2265-72.   DOI
59 Sporn MB (1996). The war on cancer. Lancet, 347, 1377-81.   DOI   ScienceOn
60 Thaker PH, Han LY, Kamat AA, et al (2006). Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med, 12, 939.   DOI   ScienceOn
61 Wojcik WJ, Neff NH (1984). gamma-Aminobutyric acid B receptors are negatively coupled to adenylate cyclase in brain, and in the cerebellum these receptors may be associated with granule cells. Mol Pharmacol, 25, 24-8.
62 Wong HP, Ho JW, Koo MW, et al (2011).Effects of adrenaline in human colon adenocarcinoma HT-29 cells. Life Sci, 88, 1108-12.   DOI
63 Yang EV, Sood AK, Chen M, et al (2006). Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res, 66, 10357-64.   DOI
64 Yang EV, Kim SJ, Donovan EL, et al (2009). Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun, 23, 267-75.   DOI
65 Cole SW, Sood AK (2012). Molecular pathways: beta adrenergic signaling in cancer. Clin Cancer Res, 18, 1201-6.   DOI
66 Botteri E, Munzone E, Rotmensz N, et al (2013): Therapeutic effect of $\beta$-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat, 140, 567-75.   DOI
67 Cakir Y, Plummer HK 3rd, Tithof PK, Schuller HM (2002). Betaadrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. Int J Oncol, 21, 153-7.
68 Cata JP, Villarreal J, Keerty D, et al (2014). Perioperative betablocker use and survival in lung cancer patients. J Clin Anesth, 26, 106-17.   DOI
69 De Giorgi V, Grazzini M, Gandini S, et al (2011). Treatment with $\beta$-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med, 171, 779-81.
70 De Giorgi V, Gandini S, Grazzini M, et al (2012). $\beta$-blockers: a new and emerging treatment for melanoma. Rec Prog Med, 103, 11-6.
71 Diaz ES, Karlan BY, Li AJ (2012). Impact of beta blockers on epithelial ovarian cancer survival. Gynecol Oncol, 127, 375-8.   DOI
72 Drell TL, Joseph J, Lang K, et al (2003). Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat, 80, 63-70.   DOI   ScienceOn
73 Entschladen F, Drell TL, Lang K, Joseph J, Zaenker KS (2004). Tumour-cell migration, invasion and metastasis: navigation by neurotransmitters. Lancet Oncol, 5, 254-8.   DOI   ScienceOn
74 Jansen L, Below J, Chang-Claude J, Brenner H, Hoffmeister M (2012). Beta blocker use and colorectal cancer risk: population-based case-control study. Cancer, 118, 3911-9.   DOI
75 Huang XY, Wang HC, Yuan Z, Huang J, Zheng Q (2012). Norepinephrine stimulates pancreatic cancer cell proliferation, migration and invasion via $\beta$-adrenergic receptor-dependent activation of P38/MAPK pathway. Hepatogastroenterology, 59, 889-93.
76 Hunt SA, Abraham WT, Chin MH, et al (2005). ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2001 guidelines for the evaluation and management of heart failure). Circulation, 112, 154-235.   DOI   ScienceOn
77 Jana D1, Sarkar DK, Maji A, et al (2012): Can cyclo-oxygenase-2 be a useful prognostic and risk stratification marker in breast cancer? J Indian Med Assoc, 110, 429-33.
78 Jansen L, Hoffmeister M, Arndt V, Chang-Claude J, Brenner H (2014). Stage-specific associations between beta blocker use and prognosis after colorectal cancer. Cancer, 120, 1178-86   DOI
79 Johannesdottir SA, Schmidt M, Phillips G, et al (2013). Use of $\beta$-blockers and mortality following ovarian cancer diagnosis: a population-based cohort study. BMC Cancer, 13, 85.   DOI
80 Kalinichenko VV, Mokyr MB, Graf LH Jr, Cohen RL, Chambers DA (1999). Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a betaadrenergic receptor mechanism and decreased TNF-alpha gene expression. J Immunol, 163, 2492-9.
81 Oliva S, Cioffi G, Frattini S, et al.; Italian Cardio-Oncological Network (2012). Administration of angiotensin-converting enzyme inhibitors and $\beta$-blockers during adjuvant trastuzumab chemotherapy for nonmetastatic breast cancer: marker of risk or cardioprotection in the real world? Oncologist, 17, 917-24.   DOI
82 Nagmani R, Pasco DS, Salas RD, Feller DR (2003). Evaluation of beta-adrenergic receptor subtypes in the human prostate cancer cell line-LNCaP. Biochem Pharmacol, 65, 1489-94.   DOI
83 Neeman E, Zmora O, Ben-Eliyahu S (2012). A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin Cancer Res, 18, 4895-902.   DOI
84 Nkontchou G, Aout M, Mahmoudi A, et al (2012). Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis. Cancer Prev Res, 5, 1007-14.   DOI
85 Packer M, Bristow MR, Cohn JN, et al; US Carvedilol Heart Failure Study Group (1996). The effect of carvedilol on morbidity and mortality in patients with chronic heart failure, N Engl J Med, 334, 1349-55.   DOI
86 Palm D, Lang K, Niggemann B, et al (2006). The norepinephrinedriven metastasis development of PC-3 human prostate cells in BALB/c nude mice is inhibited by $\beta$-blockers. Int J Cancer, 118, 2744-9.   DOI   ScienceOn
87 Park PG, Merryman J, Orloff M, Schuller HM (1995). Beta adrenergic mitogenic signal transduction in peripheral lung adenocarcinoma: Implications for individuals with preexisting chronic lung disease. Cancer Res, 55, 3504-8.
88 Shakhar G, Ben-Eliyahu S (2003). Potential prophylactic measures against postoperative immune-suppression: could they reduce recurrence rates in oncological patients? Ann Surg Oncol, 10, 972-92.   DOI
89 Seicean S, Seicean A, Alan N, et al (2013). Cardioprotective effect of $\beta$-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail, 6, 420-6.   DOI
90 Shakhar G, Ben-Eliyahu S (1998). In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J Immunol, 160, 3251-8.
91 Shan T, Ma Q, Zhang D, et al (2011). $\beta$2-adrenoceptor blocker synergizes with gemcitabine to inhibit the proliferation of pancreatic cancer cells via apoptosis induction. Eur J Pharmacol, 665, 1-7.   DOI
92 Shang ZJ, Liu K, Liang de F (2009). Expression of beta2- adrenergic receptor in oral squamous cell carcinoma. J Oral Pathol Med, 38, 371-6.
93 Shin VY, Wu WK, Chu KM, et al (2007). Functional role of beta-adrenergic receptors in the mitogenic action of nicotine on gastric cancer cells. Toxicol Sci, 96, 21-9.
94 Sloan EK, Priceman SJ, Cox BF, et al (2010). The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res, 70, 7042-52.   DOI
95 Sood AK, Bhatty R, Kamat AA, et al (2006). Stress hormonemediated invasion of ovarian cancer cells. Clin Cancer Res, 12, 369-75.   DOI   ScienceOn
96 Zhang D, Ma Q, Wang Z, et al (2011). $\beta$2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NF${\kappa}B$ pathway. Mol Cancer, 10, 146.   DOI
97 Yang EV (2010). Role for catecholamines in tumor progression: Possible use for $\beta$-blockers in the treatment of cancer. Cancer Biol Ther, 10, 30-2.   DOI
98 Zhang D, Ma QY, Hu HT, Zhang M (2010). $\beta$2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NF${\kappa}B$ and AP-1. Cancer Biol Ther, 10, 19-29.   DOI