Propranolol and the Stress–Cancer Axis

Blocking the stress hormones

This chapter is based in part on the chapter on propranolol from the book by Jeffrey Dach, MD entitled Cracking Cancer Toolkit.(1) Chronic stress activates the sympathetic nervous system, which secretes catecholamines which feed cancer growth.(2, 3) Accumulating data indicate that the psychological stress caused by chronic stressors is a major risk factor for cancer occurrence, growth and metastasis.(2, 3) “Experimental analyses with in vivo animal models have now shown that behavioral stress can accelerate the progression of breast, prostate, and ovarian carcinomas, neuroblastomas, malignant melanomas, pancreatic carcinoma and some hemopoietic cancers such as leukemia. In many of these experimental models, the biological effects of stress could be efficiently blocked by beta-adrenergic antagonists and mimicked by pharmacologic beta agonists.”(4) In a mouse ovarian cancer model chronic stress promoted cancer progression.(5) Similarly chronic stress enhanced metastatic spread in a mouse model of Lewis lung cancer. (6) Partecke et al demonstrated that chronic stress increases experimental pancreatic cancer growth, reduces survival and could be antagonized by beta-adrenergic receptor blockade.(7)

Anticancer pathways and mechanisms

Propranolol is a commonly used non-selective, beta-adrenergic receptor antagonist used in the treatment of hypertension, angina, anxiety, cardiac arrhythmia, hyperthyroidism, essential tremor and as a prophylaxis against migraine, variceal bleeding and myocardial infarction. First developed in the 1960s, the drug is now available globally in generic form and is on the WHO List of Essential Medicines.(8)

Propranolol is a well-known and widely used beta-blocker with a range of actions which are of interest in an oncological context. Propranolol displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumor cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects exist, in multiple cancer types. (8)

Propranolol is a non‑selective beta‑adrenergic blocker that interferes with stress‑related signaling, which many tumors exploit to grow and spread. Key proposed anticancer actions include:

• Inhibiting angiogenesis (tumor blood‑vessel formation) and slowing tumor growth in preclinical models.(8)

• Reducing tumor cell proliferation, migration, and invasion in several solid tumor types (breast, melanoma, ovarian, oral, angiosarcoma, others).(9)

• Inducing apoptosis and autophagy through pathways such as ROS‑dependent JNK activation in ovarian cancer cells.​(9)

• Modulating the tumor microenvironment by decreasing myeloid‑derived suppressor cells and enhancing T‑cell infiltration, thereby promoting an anti‑tumor immune milieu.(10, 11)

• Upregulating PD‑L1 on tumor‑associated macrophages and enhancing the effect of immune checkpoint blockade (e.g., anti‑CTLA‑4).(10, 11)

Figure 1. Anticancer effects of Propranolol

These multimodal effects position propranolol as a potential adjuvant that targets angiogenesis, metastatic cascades, and immune evasion rather than directly killing cancer cells alone.

Propranolol blocks activation of the sympathetic nervous system. In a murine model of acute lymphoblastic leukemia (ALL) Lamkin et al found that chronic stress enhanced tumor growth and dissemination and that the effect could be inhibited by propranolol.(12) In a mouse model, Sloan et al reported that stress induced beta-adrenergic signaling increased macrophage infiltration into the tumor (M2 polarization), induced pro-metastatic gene expression and induced a 30-fold increase in distant metastatic lesions. (13) In this study, pharmacologic activation of β-adrenergic signaling induced similar effects, and treatment of stressed animals with the β-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues.

Beta-adrenergic receptors are overexpressed in many cancers, playing a key role in invasion and metastatic behavior.(14) In addition, beta-adrenergic signaling plays a role in the tumor micro-environment, inducing immunosuppression, and enhancing tumor evasion by impairing host anti-tumor immunity. (15) Infiltration by nerve fibers is a feature of the tumor microenvironment that is associated with aggressiveness and involves nerve growth factor (NGF) production by cancer cells.(16) Catecholamines expressed in the tumor microenvironment greatly potentiate the pro-inflammatory milieu. Adrenergic signaling impairs anti-tumor CD8+ T cell responses which is reversed by propranolol.(15) Propranolol down-regulates hexokinase 2 and inhibits glucose metabolism.(17, 18) In a late stage breast cancer patient treated with neoadjuvant propranolol, propranolol decreased the expression of the pro-proliferative and pro-survival markers, while increasing pro-apoptotic p53 expression.(18) In addition, propranolol has pro-apoptotic activity in cancer cells lines independent of p53 status.(19)

Neuroblastoma is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. Wolter et al demonstrated that propranolol inhibited growth of a panel of fifteen neuroblastoma cell lines and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, and not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro.(19) Furthermore, β-blockers increase the response to chemotherapy via direct antitumor and anti-angiogenic mechanisms in neuroblastoma. (20)

The most important function of propranolol acting via multiple mechanisms is to reduce metastatic spread. (21) Propranolol has been shown to inhibit the expression of the tissue remodeling factor matrix metalloproteinase-2 (MMP-2), MMP-9 and the pro-angiogenic vascular endothelial growth factor (VEGF) (22-24) The anti-angiogenic effect of propranolol, via down-regulation of VEGF has also been shown in a range of cancer cell lines including nasopharyngeal carcinoma, melanoma, pancreatic cancer, leukemia, head and neck squamous cell carcinoma and infantile hemangiomas. (8) Guo et al observed that norepinephrine promoted the invasiveness of a pancreatic cell line in a concentration dependent manner and that norepinephrine increased the expression of MMP-2, MMP-9, and VEGF.(24) In this model these effects were inhibited by propranolol. Xia et al demonstrated that catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages.(25) Park et al showed that hypoxia-inducible factor 1α (HIF-1α) expression is upregulated by norepinephrine and abrogated by propranolol. (26, 27)

Propranolol reduces migratory activity of breast cancer cells. In a breast cancer model the combination of metformin and propranolol reduced cancer progression, metastases, and reduced migratory and invasive behavior of cancer cells.(28) In this study the metabolic pathway of the cancer cell was skewed away from mitochondrial oxidative phosphorylation and towards glycolysis. In an experimental model, Brohee et al demonstrated that propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression.(29)

In several cancer cell lines propranolol exerts synergistic anti-tumor activity when combined with conventional chemotherapy. (8, 20) Pasquier et al demonstrated that propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents.(30)

Clinical studies

Chang et al reviewed the use of propranolol in a database of 24,238 patients over a 12-year follow-up period. (31) These authors reported that propranolol treatment significantly lowered the risk of cancers of the head and neck (HRL 0.58), esophagus (HR:0.35), stomach (HR: 0.54) colon (HR 0.68) and prostate cancer (HR:0.52).

A 2025 systematic review of 31 studies (7 RCTs, 4 systematic reviews, 20 meta‑analyses) concluded that propranolol may improve cancer outcomes, especially when given around the time of surgery to reduce recurrence risk. (32) Observational and exploratory clinical data in melanoma suggest that β‑blocker exposure, including propranolol, is associated with lower recurrence and mortality in patients with thick cutaneous melanoma.(33)

In an observational study of 800 women who underwent removal of a triple-negative breast cancer, the hazard ratio for women on beta-blockers was 0.32 for metastases and 0.42 for death from breast cancer, compared to controls not on beta-blockers.(34) Melhem-Bertrandt reported relapse-free survival in a cohort of women using beta-blockers (HR=0.32). (35)

In a meta-analysis of 4 studies the risk of death from breast cancer was reduced by half with the use of beta-blockers (HR 0.5; 95% CI 0.32-0.8). (36) In a meta-analysis of 13 studies evaluating the use of beta-blockers in early stage breast cancer, the use of beta-blockers was associated with a significant improvement in the recurrence free survival (RFS) in the overall population (HR 0.73; 95% CI, 0.56-0.96; P = 0.025) and in patients with triple-negative disease (HR 0.53; 95% CI, 0.35-0.81; P = 0.003).(37)

Data from a National Cancer Registry demonstrated that the cumulative probability of breast cancer-specific mortality was significantly lower for propranolol users compared with matched nonusers (hazard ratio, 0.19; 95% CI, 0.06 to 0.60). (38) A long term epidemiological study of breast cancer patients demonstrated that those patients receiving propranolol had a 57% reduction in distant metastases and a 71% reduced risk of dying from breast cancer compared to control patients.(39) In a 10 year follow up study of patients with breast cancer, patients treated with beta-blockers showed a significant reduction in metastasis development (p=0.026), tumor recurrence (p=0.001), and longer disease free interval (p=0.01).(39)

In patients with ovarian cancer users of non-selective beta blockers had more than double the overall survival time when compared to non-users (90 months vs. 38.2 months, p<0,001).(40) In a retrospective evaluation of 1971 patients with multiple myeloma, the intake of beta-blockers was associated with a reduced risk of disease-specific death (0.53, 95% CI 0.42-0.67 in comparison to non-BB).(41) Multivariable analysis showed the same pattern for overall survival. In a non-randomized prospective study in patients with melanoma, the use of propranolol (80 mg daily) at the time of diagnosis was significantly inversely associated with recurrence of melanoma (80% risk reduction; hazard ratio, 0.18; 95% CI, 0.04-0.89; P = .03).(33)

Types of cancers propranolol may be beneficial for

It is likely that propranolol is effective against a broad range of cancers but may have particular activity against the following tumors: neuroblastoma, breast, melanoma, angiosarcoma, lung cancer, multiple myeloma, cervical cancer, hepatocellular carcinoma, ovarian cancer, prostate cancer, pancreatic cancer and brain sarcoma.(1, 8) In light of the positive clinical experience of propranolol in the treatment of infantile hemangioma, most recently confirmed in a large multi-center randomized controlled trial, (42) and evidence of beta-adrenergic receptor expression in a range of vascular tumors including angiosarcomas propranolol is indicated in the management of these tumors.(43)

Dosing and cautions

The anti-hypertensive dose of propranolol is in the range 160 – 240 mg/day, starting at 80 mg and increasing as required to a maintenance dose that is generally 160 mg – 240 mg.(8) In patients with cancer we suggest a starting dose of 20 mg twice a day increased to 80 mg twice daily as tolerated. Propranolol should be avoided in patients with severe asthma, uncontrolled heart failure, and those with symptomatic bradycardia. Sudden termination of treatment is not advised.

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