Immunological and pleiotropic effects of individual β-blockers and their relevance in cancer therapies

Figures & data

Table 1. Pleiotropic effects of widely used β-blockers.

Drug name	Subclass	Receptor antagonism selectivity	Clinical benefit	Preclinical benefit^§	Endothelial NO release stimulation	NK cell normalizing effect	ISA	Vasodilating function
Propranolol	1st-gen	β1, β2	+	+	+** [4]	+ [5]	−	+ [4]
Carvedilol	3rd-gen	α1, β1, β2	+	+	++* [3]	NA	−	+
Nebivolol	3rd-gen	β1	NA	+	++* [3]	NA	−	+
Nadolol	1st-gen	β1, β2	NA	+	−	+ [6]	−	−
Labetalol	3rd-gen	α1, β1, β2	NA	−	−	NA	−	+
Pindolol	1st-gen	β1, β2	NA	NA	−	NA	+	−
Acebutolol	2nd-gen	β1	NA	NA	−	NA	+	−
Timolol	1st-gen	β1, β2	−	NA	−	NA	−	−
Atenolol	2nd-gen	β1	−	−	−	NA	−	−
Metoprolol	2nd-gen	β1	−	−	−	NA	−	−
Bisoprolol	2nd-gen	β1	−	NA	−	NA	−	−
Butoxamine		β2	NA	−	−	NA	−	−

ISA: intrinsic sympathomimetic activity; NA: not individually assessed by published studies.

§Details of the clinical and preclinical anticancer benefits are summarized in Table 2.

*Marked endothelial nitric oxide (NO) release stimulation effect.

**The extent of endothelial NO release stimulation by propranolol is, although significant,[4] only nominal compared to carvedilol and nebivolol.[3]

‘+’: Minimum one account of published confirmation of the activity.

‘−’: Confirmed lack of the activity.

Table 2. Selected clinical and preclinical studies on the effects of individual β-blockers.

Clinical
Tumor type	Study name	Total patients (patients on β-blockers)	Study outcome
All sites: retrospective	Lin et al. (2015) [14]	13,542 (carvedilol: 6,771, nonuse: 6,771)	Long-term use of carvedilol with mean follow-up of 5.17 years led to reduced risk of cancer at all sites versus non-users (HR 0.74, 95%CI: 0.63–0.87, p < 0.001). Maximum risk reduction observed with stomach (HR 0.30: 0.14–0.63) and lung (HR 0.59: 0.37–0.94) cancers
Breast: retrospective	Barron et al. (2011) [12]	5801 (propranolol: 70, atenolol: 525)	Only propranolol use, not atenolol, showed reduced cancer-specific mortality risk (HR 0.19: 0.06–0.60), local invasiveness (OR 0.24: 0.07–0.85), and metastasis risk (OR 0.20: 0.04–0.88)
Breast: retrospective	Childers et al. (2015) [15]	291 (not distinguished)	Random effects meta-analysis across 4 clinical studies revealed significant reduction of cancer death (HR 0.50: 0.32–0.80), and nonsignificant reduction of recurrence risk (HR 0.67: 0.39–1.13) across 5 clinical study reports
Pancreatic: randomized, prospective	Battacharrya et al. (2015) [13]	23 (GemNab vs. PEGemNab): PE = propranolol + etodolac	Combined use of propranolol/etodolac with gemcitabine/paclitaxel (GemNab) led to increased progression-free survival (7.2 vs. 11.8 months) and overall survival (10.5 vs. 15.9 months) compared to GemNab treatment alone
Preclinical
Tumor type	Study name & cytotoxin investigated	β-Blockers tested	Study outcome
Neuroblastoma: in vitro & human neuroblastoma MYC oncogene (MYCN) transgenic mouse model with competent immunity	Pasquier et al. (2013) [1]: Vincristine	Propranolol, atenolol, metoprolol, nebivolol, carvedilol, labetalol, butoxamine	Only carvedilol, nebivolol, and propranolol showed in vitro chemopotentiating effects with vincristine. In vivo, four-fold increase in median survival was observed with carvedilol cotreatment compared to vincristine treatment alone, which was accompanied by enhanced angiogenesis inhibition (p < 0.001) and tumor regression
Post-surgery metastatic effects. Breast: MADB106 in F344 rats	Avraham et al. (2010) [6]: Immunostimulation by IL-12	Nadolol (4.5 mg/kg) with indomethacin (4 mg/kg)	Surgery stress increased lung tumor retention (LTR) by seven-fold compared to no-surgery control. Nadolol/indomethacin (NI) treatment reduced the effect to three-fold (p < 0.0003). Combining NI with IL-12 treatment eliminated the surgery effect. Normalization of the number of pulmonary NK cells and individual NK cytotoxicity was responsible for the CP effect
Doxorubicin-resistant breast: Hs578T-Dox in vitro	Jonsson et al. (1999) [16]: Doxorubicin	Carvedilol	Multidrug resistance by P-glycoprotein is inhibited by carvedilol. Carvedilol, similar to verapamil, reduced the doxorubicin LD50 of Hs578T-Dox from 200 mg/L to 10 mg/L. by inhibiting P-glycoprotein
Breast: orthotopic MDA-MB-231 in NMRI-Foxn1nu (NMRI) immune-deficient nude mice	Pasquier et al. (2011) [17]: 5-flourouracil (5-FU) and paclitaxel	Propranolol	Combining propranolol use with 5-FU or paclitaxel improved the median survival by 19% and +79%, respectively, compared to the cytotoxin use only

Priviero FB, Teixeira CE, Toque HA, et al. Vasorelaxing effects of propranolol in rat aorta and mesenteric artery: a role for nitric oxide and calcium entry blockade. Clin Exp Pharmacol Physiol. 2006;33(5–6):448–455.

 PubMed Web of Science ®Google Scholar

Kanemi O, Zhang X, Sakamoto Y, et al. Acute stress reduces intraparenchymal lung natural killer cells via beta-adrenergic stimulation. Clin Exp Immunol. 2005;139(1):25–34.

 PubMed Web of Science ®Google Scholar

Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, et al. Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation. 2003;107(21):2747–2752.

 PubMed Web of Science ®Google Scholar

Avraham R, Benish M, Inbar S, et al. Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor progression. Brain Behav Immun. 2010;24(6):952–958.

 PubMed Web of Science ®Google Scholar

Lin CS, Lin WS, Lin CL, et al. Carvedilol use is associated with reduced cancer risk: a nationwide population-based cohort study. Int J Cardiol. 2015;184:9–13.

 PubMed Web of Science ®Google Scholar

Barron TI, Connolly RM, Sharp L, et al. Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol. 2011;29(19):2635–2644.

 PubMed Web of Science ®Google Scholar

Childers WK, Hollenbeak CS, Cheriyath P. Beta-blockers reduce breast cancer recurrence and breast cancer death: a meta-analysis. Clin Breast Cancer. 2015;15(6):426–431.

 PubMed Web of Science ®Google Scholar

Bhattacharyya GS, Babu KG, Bondarde SA, et al. Effect of coadministered beta blocker and COX-2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) paclitaxel. J Clin Oncol. 2015;33(suppl3; abstr 302).

 Google Scholar

Pasquier E, Street J, Pouchy C, et al. beta-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. Br J Cancer. 2013;108(12):2485–2494.

 PubMed Web of Science ®Google Scholar

Jonsson O, Behnam-Motlagh P, Persson M, et al. Increase in doxorubicin cytotoxicity by carvedilol inhibition of P-glycoprotein activity. Biochem Pharmacol. 1999;58(11):1801–1806.

 PubMed Web of Science ®Google Scholar

Pasquier E, Ciccolini J, Carre M, et al. Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget. 2011;2(10):797–809.

 PubMed Web of Science ®Google Scholar