Beta-Blockers as Anti-metastatic Drugs
- Beta-blocker use has been shown to reduce metastasis formation and extend life in seven cancer types: colon, mammary, melanoma, ovarian, prostate, non-small cell lung, hepatocellular.
- Earlier use of beta-blockers increases efficacy, but improvement in life span can be seen at nearly every stage of cancer when used in combination with conventional treatment.
- Patients at heightened risk of cancer and patients in remission could be optimal candidates for beta-blocker use as a cancer prophylactic.
- Any clinically given dosage seems to be effective, whereas unselective beta-blockers (e.g. propranolol) are more effective than cardioselective beta-blockers (e.g. atenolol). Propranolol use drops the five-year cumulative probability of breast cancer–specific mortality from 26.8% to 9.4% .
More than 90% of cancer deaths are caused by metastasis formation rather than the primary tumor . Active migration of tumor cells is an essential prerequisite for invasion and metastasis formation. Norepinephrine is the most potent activator of cell migration as evidenced in colonic [2,20], mammary , and prostate  cancer cells. This increase is mediated predominantly by beta-2 adrenergic receptors and can therefore be inhibited by clinically established non-selective beta-blockers such as propranolol. The in vivo relevance of these experimental results was confirmed by mice xenograft models using prostate  and breast cancer . Most strikingly, retrospective analyses of data from patients with several types of cancer showed that beta-blockers significantly reduce metastasis formation and consequently prolong the survival time of these patients. Results were obtained in epidemiological studies on breast cancer [7-10], melanoma [11-13], ovarian cancer , prostate cancer [15, 16], non-small cell lung cancer , and hepatocellular cancer  patients. Furthermore, a meta-analysis of these studies provided evidence that the use of beta-blockers can be associated with the prolonged survival of cancer patients, especially in patients with early-stage cancer treated primarily with surgery .
1. Sporn MB. The war on cancer. Lancet 1996; 347: 1377-1381.
2. Masur K, Niggemann B, Zänker KS, Entschladen F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res 2001; 61: 2866-2869.
3. Drell TL, Joseph J, Lang K, Niggemann B, Zänker KS, Entschladen F. Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat 2003; 80: 63-70.
4. Lang K, Drell TL, Lindecke A, Niggemann B, Kaltschmidt C, Zänker KS, Entschladen F. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer 2004; 112: 231-238.
5. Palm D, Lang K, Niggemann B, Drell TL, Masur K, Zänker KS, Entschladen F. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer 2006; 118: 2744-2749.
6. Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 2010; 70: 7042-7052.
7. Powe DG, Voss MJ, Zänker KS, Habashi HO, Green AR, Ellis IO, Entschladen F. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 2010; 1: 628-638.
8. Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta Blockers and Breast Cancer Mortality: A Population-Based Study. J Clin Oncol 2011; 29: 2635-2644.
9. Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 2011; 29: 2645-2652.
10. Botteri E, Munzone E, Rotmensz N, Cipolla C, De Giorgi V, Santillo B, Zanelotti A, Adamoli L, Colleoni M, Viale G, Goldhirsch A, Gandini S. Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat 2013; 140: 567-75.
11. De Giorgi V, Grazzini M, Gandini S, Benemei S, Lotti T, Marchionni N, Geppetti P. Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med 2011; 171: 779-781.
12. Lemeshow S, Sorensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, Lesinski GB, Jackson R, Glaser R. beta-Blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomarkers Prev 2011; 20: 2273-2279.
13. De Giorgi V, Gandini S, Grazzini M, Benemei S, Marchionni N, Geppetti P. Effect of β-Blockers and Other Antihypertensive Drugs On the Risk of Melanoma Recurrence and Death. Mayo Clin Proc 2013; 88: 1196-203.
14. Diaz ES, Karlan BY, Li AJ. Impact of beta-blockers on epithelial ovarian cancer survival. Gynecol Oncol 2012; 127: 375-378.
15. Grytli HH, Fagerland MW, Fosså SD, Taskén KA, Håheim LL. Use of beta-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 2012; 73: 250-260.
16. Grytli HH, Fagerland MW, Fosså SD, Taskén KA. Association between use of beta-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur Urol 2014; 65: 635-641.
17. Wang HM, Liao ZX, Komaki R, Welsh JW, O'Reilly MS, Chang JY, Zhuang Y, Levy LB, Lu C, Gomez DR. Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann Oncol 2013; 24: 1312-1319.
18. Nkontchou G, Aout M, Mahmoudi A, Roulot D, Bourcier V, Grando-Lemaire V, Ganne-Carrie N, Trinchet JC, Vicaut E, Beaugrand M. Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis. Cancer Prev Res (Phila) 2012; 5: 1007-14.
19. Choi CH, Song T, Kim TH, Choi JK, Park JY, Yoon A, Lee YY, Kim TJ, Bae DS, Lee JW, Kim BG. Meta-analysis of the effects of beta blocker on survival time in cancer patients. J Cancer Res Clin Oncol. 2014, 140: 1179-1188.
20. Jansen, L.; Hoffmeister, M.; Arndt, V.; Chang-Claude, J.; Brenner, H. Stage-specific associations between beta blocker use and prognosis after colorectal cancer. Cancer 2014, 120, 1178–1186.