Propranolol is a beta-blocker medication. Propranolol, like other beta-blockers, works by altering how the body reacts to certain nerve impulses, including those in the heart. It lowers heart rate and makes it easier for the heart to pump blood throughout the body. Propranolol is a beta-blocker (non-selective beta-adrenergic receptor antagonist) that some integrative oncologists use off-label for cancer treatment. Off-label use refers to a drug’s application for a disease or condition that the FDA has not yet approved. Every state in the United States allows drugs to be used off-label as long as there is sufficient evidence to support their use. It works by preventing norepinephrine and epinephrine from binding to receptors. Beta receptors are classified into three types: beta1 (1) receptors, beta2 (2) receptors, and beta3 (3) receptors. When neurotransmitters are prevented from binding to receptors, the effects of adrenaline (epinephrine) are inhibited. This action relaxes the heart and causes it to beat more slowly, reducing the amount of blood the heart must pump. This action improves the heart’s pumping mechanism over time.
Anticancer activity
Evidence from lab, animal, and human studies and clinical data suggest that propranolol has potent anticancer effects. An extensive review published in 2016 discovered the following products.
1.Inhibits cancer cell growth and invasion, reducing proliferation and increasing cell death (apoptosis)
2.It inhibits tumour angiogenesis (development of new blood vessels)4(Hefner & Csef, 2016)
In preclinical studies, beta-blockers sensitised ovarian cancer cells to chemotherapeutic agents, enhancing chemotherapy effects. 28
In preclinical studies, propranolol reduced proliferation, migration, invasion, and metastasis when combined with metformin.
Stress and Beta-blockers
Chronic stress sets off a chain of internal events that protects cancer cells from being destroyed automatically when they break away from the primary tumour. Increased epinephrine and norepinephrine (stress hormones) levels allow malignant cells to safely leave the primary tumour, avoid cell death, and progress to the next stage of metastasis and progression. Norepinephrine activates Src, a gene that regulates cancer cell survival proteins when it binds to the beta-adrenergic (ADRB) receptor on tumour cells. This activation sets off a chain reaction within cells, promoting cell survival, mobility, invasion of neighbouring tissue, and new blood vessels forming to supply the tumour. Beta-blockers obstruct the ADRB receptor, preventing it from being activated by norepinephrine.
1.Propranolol prevented the “priming effect” of repeated social disruption stress, which causes natural killer (NK) cells to increase in both number and cell-killing activity1(Tarr et al., 2012)
2.Effects on ovarian cancer: A 2015 study discovered that stress hormones promote the progression of ovarian and other cancers and that beta-blockers may be a new way to combat this effect.
When mice with ovarian cancer are stressed, their tumours grow and spread faster. Propranolol can counteract this effect2(Watkins et al., 2015)
3.Propranolol inhibited the activity of hexokinase-2, an enzyme essential for tumour metabolism.3 (Rivero et al., 2017)
In cell studies, salbutamol inhibited tumour cell invasion and reduced the expression of pro-metastatic genes4 (Choy et al., 2016)
Administration
Propranolol is a prescription medication that comes in standard and extended-release tablets, an oral solution, and an IV injection. It is available in generic form all over the world. The cash price for sixty 40-mg tablets is estimated to be between $40 and $75. Prescription drug discount apps such as GoodRX offer substantial savings.
Take this medication orally, usually 2 to 4 times per day, or directed by a doctor. Take this medication 30 minutes before eating (and at bedtime if taking four times daily). Use a medication-measuring spoon or device to measure the liquid medication.
Clinical Trials
An extensive review published in 2016 discovered that propranolol has anti-metastatic effects in breast and ovarian cancers. Evidence suggests that propranolol works at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response.
1.Reduced Metastasis
Lowered the rate of metastasis in breast and other cancers; one study discovered that propranolol might reduce the formation of brain metastases in patients with triple-negative breast cancer.5(Pasquier et al., 2011)
According to a 2016 review, propranolol should be added to the standard of care for nonmetastatic cancers as a strategy to reduce the rate of metastasis6(Pasquier et al., 2016).
2.Enhancer of Conventional treatments
Propranolol increased the sensitivity of some cancers to certain chemotherapy drugs; use increased the effectiveness of 5-FU and paclitaxel in breast cancer treatment19.
In case of studies, radiotherapy and chemoradiotherapy combinations with propranolol were found to be more effective2(Choi et al., 2014)
3 Impact on survival.
Prolonged survival of cancer patients who use, particularly those with early-stage cancer who are treated primarily with surgery3(Botteri et al., 2013)
Angiosarcoma: Seven patients with advanced/metastatic/recurrent angiosarcoma had longer progression-free and overall survival7(Barron et al., 2011)
Breast cancer survival rates are mixed:
1.Postmenopausal women undergoing surgery for early primary triple-negative breast cancer have a higher chance of survival and a lower risk of metastasis8. (Heitz et al., 2017)
2.Breast cancer progression and mortality have been reduced in some studie9s.
3.In one meta-analysis7, there was a reduction in breast cancer deaths but not in overall mortality.
4.There is no survival advantage in other large pools.
5.Heart toxicity was reduced, and survival was improved in female breast cancer patients receiving trastuzumab/anthracycline treatment.
Ovarian cancer: Longer overall survival among women with epithelial ovarian cancer;12 reviews concluded that beta-blockers, particularly nonselective beta-blockers, provided a significant survival advantage,13 while selective beta-blockers provided no benefit10(Pérez Piñero et al., 2012)
Pancreatic Cancer: A small study found that adding propranolol/etodolac (a nonsteroidal anti-inflammatory drug, or NSAID) to treat gemcitabine and albumin-bound (nab) paclitaxel increased progression-free survival.
Beta-blocker can slow the spread of cancer.
In the randomised controlled trial, 64 women were randomly assigned to receive either propranolol; a beta-blocker used to treat cardiac disease and anxiety disorders, or a placebo. They were then followed from the time of diagnosis until after the breast cancer surgery. The study’s findings revealed that just one week of beta-blocker therapy inhibited cancer invasion and had a protective effect against cancer spread.
Toxicity
Insomnia, fatigue, cold extremities, and Raynaud’s syndrome are all common side effects. Nausea, vomiting, and diarrhoea are less common side effects. PRO has been linked to heart failure, heart block, hypotension, worsening psoriasis, asthma, and psychosis. In general, the initiation of PRO may result in mild adverse effects that resolve during dose titration to a stable level. Treatment should not be abruptly discontinued, especially in patients with ischaemic heart disease; in such cases, the dose should be tapered rather than short stopped. On the other hand, PRO has a favourable toxicology profile and can be used for long-term treatments lasting several years.
Side effects:
1.Reduced risk of heart failure and markers of cardiotoxicity in anthracycline chemotherapy patients, particularly when carvedilol is used.
2.Cardiotoxicity was reduced, and survival was improved in female breast cancer patients receiving trastuzumab/anthracycline treatment.
3.Reduced emotional distress in cancer patients who have recently been diagnosed.
4.In a small study of people with locally advanced pancreatic cancer who received gemcitabine and nab-paclitaxel with the addition of a propranolol/etodolac regimen, pain and neuropathy were reduced, but weight gain was increased.
5.In a small study of cancer patients with progressive weight loss due to solid malignant tumours, resting energy expenditure was reduced.
Cautions
Propranolol has a low toxicity profile and can be used in long-term treatment for many years. However, some precautions should be taken:
Calcium-channel blocking drugs: Because of the adverse inotropic and chronotropic action of these drugs, patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction (heart attack) should exercise caution when taking propranolol with calcium-channel blocking drugs, particularly IV verapamil (actions affecting the force of contractions or heart rate and rhythm)
It is not recommended to stop using suddenly, especially if someone has ischemic heart disease. In this case, taper the dose gradually.
Drug interaction
Drug interactions can alter the way medications work or put at risk for serious side effects. This document does not include every possible drug interaction. To share with the doctor and pharmacist, keep a list of all the products use (including prescription/nonprescription drugs and herbal products). Do not start, stop, or change the dosage of any medications without first consulting a doctor. A study involving both animal and human cells found that isoprenaline and salbutamol, two drugs that stimulate the beta-adrenergic receptor, unexpectedly inhibited breast cancer and that propranolol reversed this inhibition9.
Conclusion
There is substantial data from in vitro, animal, and human studies indicating that PRO has multiple clinically relevant anticancer effects. Several approaches used to treat cancer also attack normal cells, necessitating more effective treatments that reduce toxicity to normal cells while increasing treatment success rates. Beta-blockers have been studied in cancer for their antagonist action on the adrenergic system via inhibition of beta-adrenergic receptors. Overall, data suggest that propranolol may be used as a supplement for treating various types of cancer due to its ability to improve cancer outcomes by lowering cancer cell proliferation rates. Preclinical evidence suggests that beta-blockers can be protective against cancer progression. We undertook a meta-analysis of epidemiological and perioperative clinical studies to investigate the association between beta-blocker use and cancer recurrence (CR), disease-free survival (DFS), and overall survival (OS).
Keywords: Cancer pain, Cancer treatment, Lung cancer, Prostrate cancer, Ovarian cancer, Cancer patients, Breast cancer, Cancer cell, Metastatic cancer
References
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