Beta Blockers Hold Substantial Potential For Therapeutical Interventions In Cancer

Beta Blockers and Cancer

Recently, more than 10 studies [see References 1-11], published in the last 3-4 years indicate the presence of high intratumoral concentrations of catecholamines and that these neurohormonal mediators affect key components of tumor biology such as tumor growth, angiogenesis, and migration or invasion [for details see References 12-13]. These studies suggest that blocking beta-adrenoreceptor-mediated signaling pathways might have beneficial effect in preventing cancer development, progression or complications.

Catecholamines (CAs), such as norepinephrine (NE), also known as noradrenaline, and epinephrine (EPI), also known as adrenaline, are end products of the sympathetic nervous system (SNS), a major component of the autonomic nervous system. Peripheral organs, including lymphoid tissues, receive extensive sympathetic innervation, and all immune cells, with the possible exception of T helper (Th)2 cells (in humans), express mostly beta2>>beta1 adrenoreceptors (ADRs).

The SNS and the hypothalamic-pituitary-adrenal axis (HPA) axis constitute the peripheral arms of the stress system. Acute or chronic stress and conditions such as melancholic depression, social isolation, low socioeconomic status, major injury (serious traumatic injury and major burns) or major surgical procedures are associated with increased levels of stress hormones, even though different types of stress may have different neurochemical and neurohormonal ‘signatures’ or profiles, and proportions of NE vs. EPI, vs. cortisol involved [14-17].

Below is a short summary of the studies mentioned above:

1. Depression, low social support and elevated intratumoral norepinephrine in ovarian cancer

In 2009, and more recently in February of this year, two studies by Susan Lutgendorf and colleagues, published in Brain, Behavior, and Immunity showed that low subjective social support or depression are associated with elevated intratumoral NE in ovarian cancer; and that tumor NE provides distinct information from circulating plasma concentrations. Additionally, promoter-based bioinformatic analyses revealed increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-κB/ Rel, STAT, and Ets family transcription factors [1-2].

2. The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in breast cancer

In January 2011, Ming Shi et al. published a study demonstrating that Her2 over-expression and excessive phosphorylation of ERK induce an autocrine release of EPI from breast cancer cells, resulting in up-regulation of beta2-ADR expression. Her2 is a member of the epidermal growth factor receptor (EGFR) family. Given that previous studies have shown that CAs induce beta2-ADR-mediated up-regulation of Her2 expression by activating STAT3 transcription factor, the study put forward a new positive feedback mechanism for the cross-talk between Her2 and G protein-coupled receptors (GPCR) signaling.

The study also indicates that this mechanism may generate synergistic signaling, and promoting the expression of both receptors, which in turn may induce the proliferation of breast cancer cells, secretion of CAs, and other proangiogenic and prometastatic factors, including IL-8 and VEGF. Of note, this mechanism may explain the switch from normal autoregulation (desensitization, internalization and down-regulation) of beta2-ADRs to, in fact, an up-regulation of these receptors, and a process that may further promote the tumor growth [3].

3. Catecholamines up-regulate MMP-7 expression in gastric cancer

In October 2010, Ming Shi et al. published a study indicating that up-regulation of matrix metalloproteinase (MMP)-7 expression through beta2-ADR-mediated signaling pathway is involved in invasion and metastasis of gastric cancer [4].

The sympathetic nervous system as a regulator of breast cancer metastasis
In September 2010, Erica K. Sloan and associates from the UCLA published a study demonstrating that in an orthotopic mouse model of breast cancer, physical restraint, a standardized stressor or the beta-adrenoreceptor-agonist isoproterenol increased the metastasis of primary breast tumor cells to distant tissues by 38- and 22-fold, respectively.

The beta-adrenoreceptor antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited the tumor spread. The study suggests that a direct regulation of macrophage biology by catecholamines constitute a previously unrecognized pathway by which hyperactivity of the SNS can activate a metastatic switch within a growing primary tumor [5].

4. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis

In May 2010, Anil Sood et al. reported that NE and EPI protect ovarian cancer cells from anoikis via a focal adhesion kinase (FAK)-mediated signaling pathway, initiated by beta2-ADRs and involving subsequent Src-associated phosphorylation of FAK. FAK is a non–receptor protein tyrosine kinase that localizes to focal adhesions and mediates physical attachment of cells to their extracellular matrix (ECM).

Normal cells enter apoptosis when separated from ECM and neighboring cells (a process known as anoikis). Tumor cells develop resistance to anoikis, which allows for their survival during the process of metastasis. The study identifies NE- and EPI-induced FAK activation as a novel mechanism by which stress might accelerate the pathogenesis of ovarian cancer [6].

5. A combination of beta-ADR antagonist and cyclooxygenase-2 inhibitor improves survival rates in murine models of postoperative metastasis

In March 2010, Ariella Glasner and colleagues showed that in mice, blocking beta-ADRs with propranolol, and simultaneously inhibiting prostaglandin synthesis with etodolac signiﬁcantly improves recurrence-free survival rates following 3LL or B16 primary tumor excision. The study suggests that the immediate postoperative period is critical for determining long-term tumor recurrence rates.

It also promotes the clinical testing of a new approach for reducing long-term cancer recurrence: a combined blockade of excess release of catecholamines and prostaglandins in the perioperative period. Such an approach has not been tested clinically thus far [7].

6. Norepinephrine upregulates key angiogenic factors in human melanoma, multiple myeloma and nasopharyngeal carcinoma tumor cells

In 2006, 2008 and 2009, three studies by the group of Eric Yang and Ronald Glaser from the Ohio State University Medical Center demonstrated that NE stimulates the expression of VEGF in human melanoma tumor cell lines, multiple myeloma-derived cell lines and nasopharyngeal carcinoma tumor cells. The authors also showed that NE upregulated IL-8 and IL-6 expression in human melanoma tumor cell lines and MMP-2 and MMP-9 in nasopharyngeal carcinoma tumor cells. These data suggest that CAs may affect tumor progression, in part, through upregulation of factors responsible for invasion or angiogenic responses [8-10].

7. Norepinephrine and epinephrine increase the expression of IL-6 in human ovarian carcinoma cells

In October 2007, Monique Nilsson and colleagues reported that stress mediators, such as NE and EPI increase the expression of IL-6 mRNA and protein levels in ovarian carcinoma cells, and do so through a beta-ADR/Src tyrosine kinase signaling axis. This indicates that stress-induced activation of beta-adrenergic signal transduction pathways in ovarian tumor cells can enhance expression of highly angiogenic cytokines that supports progression of disease [11].

8. Previous studies and CAs-induced tumor-related immunosuppression

Apart from direct effects (most of the studies above), CAs may affect tumor growth, indirectly through effects on the immune system. These effects include an inhibition of natural killer (NK) cell activity, a key component of the anti-tumor immunity.

Noteworthy, NK cells appear to be the most “sensitive” cells to the suppressive effect of stress, most likely due to the fact that NK cells probably possess the highest number of beta2-ARs among lymphoid cells. In addition, CAs reduce T-cell responses to mitogens, block the capacity of IFN-gamma to activate macrophages to a tumoricidal state, and suppress the generation of anti-tumor cytotoxicity of splenic Tc lymphocytes [14,18].

Of note, the amount of IL-12 available at the tumor site appears to be crucial for tumor regression, and low levels of IL-12 have been associated with tumor growth, while local overproduction of IL-10 seems to play an inappropriate immunosuppressive role [cf. Ref. 17].

Although a matter of speculation, stress may contribute to these pathologic changes given that CAs (particularly EPI) are extremely potent inhibitors of IL-12 (and, thus, the development of Th1-type cells) and up-regulators of the Th2-related cytokine IL-10, which is a potent suppressor of the effector functions of macrophages, T cells, and NK cells [14,17,19-22]. An interesting recent finding, along these lines indicates that continuous stress may disrupt immunostimulatory effects of IL-12 [23].

On the other hand, CAs are able to upregulate IL-6 production by human endothelial cells, adipocytes, the liver and skeletal muscle, and IL-8 production by monocytes, lung epithelial cells and endothelial cells, indirectly, via an effect on platelets [cf. Ref. 14]. Thus, these effects of CAs in various normal cells may act in concert with the above-mentioned effects on IL-6 and IL-8 in tumor cells, and promote angiogenesis and disease progression.

The differences between inhibitory vs. certain ‘stimulatory’ effects of CAs can be explained by some differences of systemic vs. local effects or intracellular pathways involved (e.g. cAMP may enhance transcription through cAMP-responsive element in the regulatory region of the IL-10 and IL-6 genes), and in general, by the concept developed in the 1990s that stress hormones and CAs induce a selective suppression of Th1 responses and Th1-related cellular immunity, and a Th2 shift toward humoral immunity, rather than generalized immunosuppression, as previously believed [14,17,19-22].

Thus, this unique ‘signature’ of CAs – a selective and potent inhibition of Th1, NK and cellular immune responses that are key component of the anti-tumor immunity, and an upregulation of IL-10, a potent immunosuppressive agent, along with the highly angiogenic cytokines IL-6, IL-8 and VEGF, may, overall, provide systemic and/or local (micro)environment that may enhance or promote to a great extent the growth of certain tumors.

Conclusion

An increasing body of evidence indicates that CAs through stimulation of beta-ADRs are involved in tumor development and tumor-related immunosuppression. Thus, blocking beta-adrenoreceptor-mediated signaling pathways may open a new window of opportunities, and provide new conceptual advances in the therapy of malignancies.

This may also suggest that conceptual frameworks derived from the field of neuroendocrine-immunology and studies at the interface between neurosciences, endocrinology and immunology hold substantial potential for the development of promising therapeutical interventions in common human diseases.

References

Lutgendorf SK et al. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun, 2011, 25:250.
Lutgendorf SK et al. Depression, social support, and beta-adrenergic transcription control in human ovarian cancer. Brain Behav Immun, 2009, 23:176.
Shi M et al. The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat, 2011, 25:351.
Shi M et al. Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer. Mol Cancer, 2010, 9:269.
Sloan EK et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res, 2010, 70:7042.
Sood AK et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J Clin Invest, 2010, 120:1515
Glasner A. et al., Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol, 2010, 184:2449.
Yang EV et al. 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, 2009, 23:267.
Yang EV, Donovan EL, Benson DM, Glaser R. VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine. Brain Behav Immun, 2008, 22:318.
Yang EV et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res, 2006, 66:10357.
Nilsson MB et al. Stress hormones regulate interleukin-6 expression by human ovarian carcinoma cells through a Src-dependent mechanism. J Biol Chem, 2007, 282:29919.
Thaker PH and Sood AK. Neuroendocrine influences on cancer biology (The Neuroendocrine Impact of Chronic Stress on Cancer). Semin Cancer Biol, 2008, 18:164.
Moreno-Smith M, Lutgendorf SK and Sood AK. Impact of stress on cancer metastasis. Future Oncol, 2010, 6:1863.
Elenkov IJ, Wilder RL, Chrousos GP and Vizi ES. The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev, 2000, 52:595.
Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol, 2009, 5:374.
Goldstein DS and Kopin IJ. Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: a meta-analysis. Endocr Regul, 2008, 42:111.
Elenkov IJ and Chrousos GP. Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease. Trends Endocrinol Metab, 1999, 10:359.
Ben-Eliyahu S, Page GG and Schleifer SJ. Stress, NK cells, and cancer: Still a promissory note. Brain Behav Immun, 2007, 21:881.
Elenkov IJ, Papanicolaou DA, Wilder RL and Chrousos GP Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Amer Physic, 1996, 108:374.
Panina-Bordignon P et al. Beta2 agonists prevent Th1 development by selective inhibition of interleukin-12. J Clin Invest, 1997, 100:1513.
Woiciechowsky C et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med, 1998, 4:808.
Elenkov IJ et al. Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans? J Immunol, 2008, 181:1737.
Levi B et al. Continuous stress disrupts immunostimulatory effects of IL-12 (Article in press). Brain Behav Immun (2011), doi:10.1016/ j.bbi.2011.01.014. [Epub ahead of print].

Updates

2013

A 2013 study by Qiang Lin et al. investigated the effects of chronic restraint stress (CRS) on colorectal carcinoma (CRC) progression in nude mice. The authors demonstrated that CRS increased the levels of plasma catecholamines, including epinephrine (E) and norepinephrine (NE), and stimulated the growth of CRC cell-derived tumors in vivo.

The investigators found that the adrenoceptor (AR) antagonists phentolamine (PHE, α-AR antagonist) and propranolol (PRO, β-AR antagonist) significantly inhibited the CRS-enhanced CRC cell growth in nude mice. Thus, the authors concluded that CRS promotes CRC xenograft tumor growth in nude mice by stimulating CRC cell proliferation through the AR signaling-dependent activation of ERK1/2.

2015

A 2015 study by M Coelho et al. confirmed that stress hormones affect colon-cancer cell proliferation, and suggested a prominent role for β-ARs in this process. The authors found that the catecholamine adrenaline and isoprenaline (ISO, also called isoproterenol, a synthetic non-selective beta-adrenoceptor agonist) significantly enhanced HT-29 cell (a human colon adenocarcinoma cell line) proliferation, most likely through β-ARs.

The authors concluded that their results suggested the involvement of the β-AR subtypes, β1 and β2, in promoting colon-cancer cell proliferation. Of note, in their study, propranolol (PRO), the non-selective β-AR antagonist, was the most potent β-blocker in reversing adrenaline’s effects following cell proliferation, by its ability to bind to the two subtypes, as identified in previous studies.

Another 2015 study by Hua Lu et al. was based on meta-analysis using a total of four studies including 16,825 patients with prostate cancer. The authors reported that the analysis of all studies showed that beta-blocker use was associated with reduced prostate cancer-specific mortality, without any heterogeneity between studies.

However, the authors did not observe any effect of beta-blocker use on all-cause mortality in this meta-analysis. They suggested that beta-blockers may be considered a promising therapeutic approach for adjuvant therapy in prostate cancer.

Yet another 2015 study by Jack L Watkins et al. examined the impact of beta-adrenergic blockade on clinical outcome of women with epithelial ovarian, primary peritoneal or fallopian tube cancers (collectively, EOC). Of note, usage of beta blockers was defined as any documentation of beta blocker use in the medical record during neoadjuvant (NACT) or adjuvant chemotherapy (ACT).

The authors reported a prolonged median overall survival (OS) of EOC patients receiving beta blockers, especially non-specific beta blockers (NSBB) such as propranolol. As per the authors, their study was the first to demonstrate an OS benefit in relation to beta blocker selectivity in ovarian cancer patients.

Again, according to the authors, particularly interesting was the fact that beta blocker users in this study presented at a higher stage, had increased average BMI and were more likely to be hypertensive. All of these factors were associated with decreased survival, yet those who received beta blockers had either equivalent or improved OS. Further examination revealed that NSBB users had improved OS regardless of the presence of prognostic factors or comorbidities shown to decrease OS.

2016

A 2016 review by Marisa Coelho et al. discussed the available preclinical and epidemiological evidences regarding the modulation of cancer cell proliferation by β-adrenoceptors (β-AR), with a specific focus on the putative effects of β-blockers according to their pharmacological properties.

Figure 1. Schematic representation of biased signaling of propranolol on β2-AR. Propranolol acts on β2-AR as a partial agonist by β-arrestin signaling activating MAPK pathway and as inverse agonist on the canonical Gs pathway decreasing the levels of cAMP. In the latter case is suggested the existence of two pathways downstream from cAMP: one involving a cAMP-dependent activation of MAPK signaling and another involving the PKA activation. Both pathways seem to increase the phosphorylation of transcription factors such as CREB. These evidences show that drugs acting on a unique receptor can have different efficacies depending on the signaling pathway activated, which add a new level of complexity in the study of β-blockers effects not only in cancer, in which these drugs have been gaining momentum, but also in other diseases. PRO—propranolol; cAMP—3′–5′-cyclic adenosine monophosphate; CREB—cAMP response element transcription factor; PKA—protein kinase A; MAPK—mitogen-activated protein kinase; β2-AR—β2-adrenoceptor. From: β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives, by Marisa Coelho et al. J Cancer Res Clin Oncol. 2016 Oct 5;143(2):275–291. doi: https://link.springer.com/article/10.1007/s00432-016-2278-1

As per the authors, overall, the scrutinized studies displayed strong evidence that adrenergic agonists, through multiple intracellular mechanisms, enhance tumor cell proliferation and that β-blockers can be used to reverse this effect.

The authors suggested that several issues should be addressed by future research: (1) evaluation of β-AR expression on human tumor tissues which may be an useful tool to select which patients can benefit with β-blockers treatment; (2) to characterize the β-blockers more often associated with positive outcomes and which are more likely to benefit cancer patients; (3) To characterize the properties of clinically relevant β-blockers in terms of their action on Gαs and β-arrestin-mediated signaling, given that their implications in vivo are mostly unknown.

Also in 2016 Pan Pantziarka et al. provided a review of the significant volume of data from in vitro, animal and human studies that indicate that there are multiple clinically relevant anti-cancer effects associated with propranolol (PRO). This data has been summarized and presented to make the case that PRO is a very strong candidate for repurposing as an anticancer agent.

As per the authors, while there is evidence that other drugs in the same class as have anti-cancer effects, for example carvedilol and nebivolol, PRO has both the widest range of evidence and extensive clinical use, therefore pragmatic reasons suggest that it be prioritized for further clinical research. The data are strongest for clinical trials of PRO, in combination with other agents, in the following cancer types:

Angiosarcoma
Breast cancer
Ovarian cancer
Pancreatic cancer
Neuroblastoma

Of note, the potential for synergistic interactions with other drugs has been outlined, including repurposed COX-2/PGE₂ inhibitors and a range of chemotherapeutics at both metronomic and standard dosing. The anti-metastatic properties of PRO may be particularly valuable to exploit during surgical intervention, and a number of possible combinations with other agents is discussed in this setting.

2017

A 2017 Meta-Analysis by Alexa Montoya et al. using a retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. This analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% in early stage breast cancer compared to non-users. Of note, selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation.

2019

A 2019 review by Massimo Dal Monte et al. summarized data from the literature demonstrating that propranolol may be effective at counteracting melanoma growth, and that β₃-adrenoceptors may also play a role in the pathophysiology of melanoma.

Background

Melanoma is the most aggressive skin cancer, and its progression depends on molecular alterations that select cells able to survive in an unfavorable micro-environment. Until recently, therapeutic options to treat melanoma have been limited to surgical interventions and chemotherapies in the early stage of the disease, as metastatic melanomas are often refractory to commonly used anticancer drugs. Nonetheless, tumor resistance or relapse of the melanoma lesion has been observed, suggesting the need for additional therapies to be used alone or as add-on therapies in treating melanoma.

Figure 2. Stress-induced release of catecholamines from the sympathetic nervous system and the adrenal medulla acts on tumour cells by driving their proliferation and inhibiting apoptotic cell death, thus sustaining tumour growth. Catecholamines may also recruit macrophages into the tumor mass likely through β2- and/or β3-adrenoceptors and induce M2 pro-tumourigenic phenotype presumably through β2-adrenoceptors. Catecholamines additionally act on endothelial cells to stimulate angiogenic processes possibly through β2- and/or β3-adrenoceptors. β1-AR, β1-adrenoceptor; β2-AR, β2-adrenoceptor; β3-AR, β3-adrenoceptor. From: β-Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3–adrenoceptors. Br J Pharmacol. 2019 Jul;176(14):2496-2508. doi: https://pubmed.ncbi.nlm.nih.gov/30471093/.

As per the authors of this review, targeting β-adrenoceptors may be an effective way of counteracting melanoma growth, and the possibility of introducing drugs that block β1- and β2-adrenoceptors in the management of melanoma patients is under active investigation.

According to the authors, the incorporation of β3-adrenoceptor blockers into the therapeutic armamentarium has far to go. Indeed, the currently available β3-adrenoceptor blockers pose some problems of specificity, and the pattern of receptor expression as well as the ligand pharmacological profile may differ between rodents and humans.

Thus, evidence from clinical studies is mandatory before it is decided whether β3-adrenoceptors may be effectively regarded as an additional therapeutic target.

Another 2019 review by George Kulik discussed how information on the antiapoptotic mechanisms activated by the β-2 adrenergic receptor (ADRB2) can guide clinical trials of ADRB2 antagonist propranolol as potential life-extending therapy for prostate cancer.

Figure 3. ADRB2 signaling in prostate cancer. (A) epinephrine (Epi) and norepinephrine (NE) from circulation and secreted locally by sympathetic nerves, neurodifferentiated prostate cancer cells and macrophages activate anti-apoptotic signaling in prostate cancer cells and stimulate angiogenesis and invasion; (B) Activation of ADRB2 signaling (that can be inhibited by propranolol) induces phosphorylation of PKA substrates pS133CREB, pS157VASP, p75BAD and increases expression of myeloid cell leukemia 1 (MCL-1). Dephosphorylations of vasodilator-stimulated phosphoprotein (VASP) and cAMP response element binding protein (CREB) reflect inactivation of β-2 adrenergic receptor/cAMP-dependent protein kinase (ADRB2/PKA) signaling pathway by propranolol, whereas decreased levels of MCL-1 and p75BAD predict whether propranolol will sensitize prostate cells to apoptosis. From: ADRB2-Targeting Therapies for Prostate Cancer by George Kulik, Cancers (Basel). 2019 Mar 13;11(3):358. doi: https://www.mdpi.com/2072-6694/11/3/358

As per the author, experiments in mouse models of prostate cancer and pilot clinical studies showed that the ADRB2 is an integral part of highly redundant network of signaling pathways that contribute to PC progression and therapy resistance. Moreover, analysis of the ADRB2/PKA signaling confirmed that targeted apoptosis regulatory molecules are not unique for this pathway, but instead, are shared with other signaling mechanisms that operate in advanced prostate cancer. Therefore, according to the author topology of signaling network that include ADRB2/PKA pathway should be considered when clinical trials of propranolol are designed.

And, importantly, the author suggested that to produce conclusive results, clinical trials of propranolol should use a personalized approach with stringent criteria to select patients that are expected to benefit from propranolol therapy. Active ADRB2 signaling defined by increased systemic Epi and/or increased Epi/NE in the tumors together with activation of PKA signaling pathway (phosphorylation of PKA substrates S133CREB, S157VASP and S75BAD) should be the main inclusion criterion, whereas patients that do not show activation of ADRB2/PKA pathway should be excluded.

2020

A 2020 review by Monique B Nilsson, Xiuning Le and John V Heymach outlined the preclinical and clinical evidence supporting a potential role for beta-blockers in improving the clinical outcome of lung cancer patients. The authors discussed recent evidence that strongly supports a role for β-AR signaling on lung cancer cells in facilitating multiple aspects of tumor progression including tumor cell proliferation, the acquisition of a mesenchymal and invasive phenotype, angiogenesis, immune evasion, and resistance to chemotherapy, radiation and targeted agents.

As per the authors these findings have important clinical implications as beta-blockers are well-tolerated, inexpensive, and clinically available. Of note, preclinical studies indicated that the direct effects of stress hormones on tumor cells are predominantly mediated by β2-ARs. Thus, the authors suggested that the use of cardio-selective versus nonselective beta-blockers likely have differential effects on tumor progression.

2023

A 2023 review by Zoltan Kraboth and Bernadette Kalman presented epidemiological and preclinical data concerning stress-related activation of the ß-adrenoreceptors (ß-ARs), which contributes to the formation, sequential transformation, and migration of different tumor cell types.

As per the authors our body fights stress by activating catecholamine neurotransmitters in the sympathetic nervous system. These signals exert their effects through the well-characterized α- and ß-ARs that are expressed in most tissues. In breast and lung cancer, melanoma, and gliomas, a great body of observations supports that ß-ARs are involved the downstream systems of cAMP and can play a prominent role in tumorigenesis by maintaining cell proliferation and contributing to the development of metastases.

The activation of catecholamine receptors and their downstream pathways likely is not alone sufficient to trigger but rather only modulates tumor initiation and growth through multiple mechanisms that involve the sympathetic nervous system or the tumor initiating cells, the TME, and immune regulatory cells directly.

As per the authors while the most effective anticancer beta-blockers drugs and their routes of administration and timing remain to be identified in each histological tumor type, there are also some newer groups of drugs and approaches that hold great promise in the receptor-specific manipulation of cell biology.

These new directions include chemogenetics, which may very precisely and effectively target desired receptors and their downstream signaling pathways, thereby shaping the activity of a selected cell group (e.g., neurons or tumors) via an engineered DREADD. While beta-blockers may not provide a sufficient advantage as a monotherapy and only act as adjuvants to the traditional anticancer approaches, the rapidly developing and increasingly tested chemogenetic paradigm may fulfill the hopes attached to them; namely, a very precise, selective manipulation of desired cells and their key receptor(s), which likely will represent a new direction in precision oncology.

2025

A 2025 review by Jessica O’Logbon et al. discussed that propranolol has potential as an adjunctive therapy in cancer treatment.

As per the authors, while there is some evidence indicating that propranolol may improve cancer outcomes, the timing of administration and adjunctive cancer treatment it is paired with, appear to be key factors in determining its effectiveness. Thus, the perioperative period may represent a critical window for beta-blockade to exert its beneficial effects, potentially reducing the risk of recurrence. However, the power of its use in conjunction with chemotherapy or radiotherapy is less clear, with mixed results across studies.

According to the authors future clinical trials are needed to address these uncertainties, ideally focusing on specific cancer types, patient populations, and treatment regimens to better define the role of propranolol as an adjunctive therapy. Moreover, investigations into the molecular and immunological mechanisms by which beta-blockers exert their effects will be crucial for optimising treatment strategies and identifying the patients who are most likely to benefit from beta-blockade in cancer therapy.

Another 2025 systematic review by Fangyuan Zhang et al. summarized recent evidence indicating that beta-blockers demonstrate clinically meaningful benefits when combined with immunotherapy, particularly in β2-AR+ melanoma and breast cancer, but show potential harm in pancreatic/head-neck cancers.

As per the authors, these results support preferential use of propranolol (20-40mg/day) in immunotherapy-treated melanoma, and avoidance of routine beta-blockers use in non-immunogenic tumors without adrenergic profiling. Thus, prospective trials should validate these selection criteria.

2026

A 2026 systematic review and meta-analysis by Sule Eraslan et al. summarized 94 articles included in the systematic review, and 84 in the meta-analysis comprising 603,827 patients.

The authors reported that beta-blocker use in patients with solid cancers was associated with significantly improved overall survival (OS), and progression-free survival (PFS). The greatest effects on OS were observed in patients with gastrointestinal, lung, and skin cancers. Effects appeared stronger with post-diagnostic exposure and in certain cancer subtypes, however, as per the authors, heterogeneity and the observational nature of most included studies warrant cautious interpretation. The authors concluded that beta-blocker use was associated with improved OS and PFS in patients with solid cancers.

Another 2026 meta-analysis by Suprabhat Giri et al. suggested a protective effect of beta-blockers on the development of pancreatic cancer. The pooled data showed that beta-blockers were significantly associated with a reduced incidence of pancreatic cancer. Similarly, continued use of beta-blockers after the diagnosis of pancreatic cancer was associated with improved survival. However, the use of beta-blockers prior to diagnosis of pancreatic cancer did not improve survival.

Although no survival effect could be seen in patients using beta-blockers prior to the diagnosis of pancreatic cancer, the benefit was seen in patients who continued to take beta-blockers after the diagnosis. According to the authors these findings are consistent with the biological premise that attenuation of β-adrenergic receptor-mediated signaling may modulate tumor progression in pancreatic ductal adenocarcinoma and raise the possibility that β-blockers could serve as adjunctive agents alongside established oncologic therapies.

Yet another 2026 meta-analysis by Wentong Xu et al. indicated that in patients with solid tumors who received radiotherapy, the combination of beta-blockers may be associated with an improvement in overall survival (OS).

Such benefits appeared to be specific to certain cancer types and time periods, with more apparent long-term effects in oropharyngeal cancer, which may be linked to reduced tumor recurrence and distant metastasis. As per the authors their observations suggested that the positive effects of nonselective beta-blockers (such as propranolol) may be related to their antagonism of beta2 receptors.

According to Heng Xu et al., the authors of another 2026 review, tumor cells frequently evade immune surveillance by forming an immunosuppressive microenvironment, leading to treatment resistance. As per these authors recent evidence positions the sympathetic nervous system (SNS) at the forefront of tumor immunology as a critical driver of this immune evasion.

Moreover, the SNS forms structured neuro–immune synapses with immune cells via tumor-innervating fibers, releasing norepinephrine (NE) and epinephrine (Epi) that interact with β₂-adrenergic receptors (β₂-ARs) triggering G-protein dissociation, adenylyl cyclase stimulation, and cAMP generation, which exert multifaceted regulatory effects on antitumor immunity.

All this promotes the polarization of macrophages to the M2 phenotype, hinders dendritic cell maturation, impairs natural killer (NK) cell function, fosters the differentiation of regulatory T cells (Tregs), and suppresses the effector activity of CD8⁺ T cells.

Importantly, the authors of this review summarized preclinical evidence demonstrating that the pharmacological blockade of β₂-AR signaling can reverse these immunosuppressive effects, augmenting intratumoral CD8⁺ T-cell infiltration and enhancing the efficacy of immune checkpoint inhibitors (ICIs). Thus, in summary, the authors suggested that these findings demonstrate the potential of targeting sympathetic nerve pathways as an adjunctive measure in cancer immunotherapy.

Beta Blockers Hold Substantial Potential for Therapeutical Interventions in Cancer