Page 28 - JCTR-11-4

Journal of Clinical and
Translational Research Propranolol as a treatment for HCC

mechanisms is crucial for developing targeted therapies HBV- and HCV-associated HCC. 42
to prevent or treat HCC in patients with chronic HCV
infection. 30 5. Role of propranolol in the prevention of
HCC
4. Propranolol
Propranolol has been found to suppress the growth and
4.1. Properties of propranolol proliferation of HCC cells by blocking beta-adrenergic
Propranolol (Figure 1) is a non-selective beta-adrenergic receptors, which were found to be a key regulator for
36
receptor antagonist first developed by Sir James Black cancer development. In addition, propranolol was said
in 1962 and approved for clinical use in 1964. It blocks to regulate the immune system by blocking the secretion
31
both β1 and β2 receptors, leading to reduced heart rate, of pro-inflammatory cytokines and inducing anti-tumor
43
myocardial contractility, and blood pressure. Beyond its immunity. This dual mechanism of action makes
32
cardiovascular applications, propranolol demonstrates anti- propranolol an attractive treatment option for HCC
angiogenic, anti-inflammatory, and immunomodulatory patients infected with HBV and HCV. In addition, clinical
properties. These characteristics form the basis of its investigations have shown that propranolol can increase
emerging role in oncology, including HCC. 33,34 overall survival rates and decrease tumor recurrence
in these patients. Furthermore, propranolol’s anti-
42
Due to its high lipophilicity, propranolol readily
crosses the blood-brain barrier and undergoes extensive angiogenic effects contribute to its anticancer activity. By
suppressing VEGF and HIF-1α expression, it effectively
first-pass hepatic metabolism, with approximately 25% reduces neovascularization required for tumor growth and
bioavailability. While it binds to plasma proteins at a 38,44,45
35
high rate (>90%), propranolol’s distribution across tissues, metastasis. These properties have shown promise not
including the liver, supports its potential therapeutic use in only in HCC but also in other malignancies such as breast,
41
hepatic malignancies. 35 lung, and colorectal cancers. Propranolol effectively
starves cancer cells and inhibits their ability to proliferate
Research has shown that propranolol can inhibit by targeting this critical phase of tumor development. This
β-adrenergic receptor-mediated signaling pathways, anti-angiogenic effect has been observed in breast, lung,
which are implicated in tumor cell proliferation, and colorectal cancers. Propranolol has demonstrated
migration, and angiogenesis. The drug suppresses the immunomodulatory effects that extend beyond cytokine
36
production of vascular endothelial growth factor (VEGF) suppression. Notably, it has been shown to enhance the
and hypoxia-inducible factor-1 alpha (HIF-1α), key activity of natural killer cells – key components of the innate
regulators of angiogenesis in tumors. 37,38 It also induces immune system responsible for targeting and eliminating
apoptosis in endothelial cells, thereby disrupting tumor cancer cells. By activating natural killer cells and boosting
vascularization. 39 their cytotoxic function, propranolol strengthens the body’s
Propranolol’s immunomodulatory effects are also antitumor response, offering a promising mechanism for
noteworthy. It reduces the release of pro-inflammatory its potential efficacy in cancer therapy. 40,41,46 This discovery
cytokines and enhances the activity of natural killer cells, sheds light on the potential of propranolol as an adjunct
which play a vital role in antitumor immunity. 40,41 These therapy for various cancers, including breast, lung, and
combined effects suggest that propranolol may be effective colorectal cancers. With its multiple effects on cytokine
in preventing tumor progression and recurrence in production and immune cell activity, propranolol bears
promise as a cancer-fighting agent. Propranolol can
47
reduce the expression of programmed cell death protein
1 (PD-1) and T cell immunoglobulin and mucin domain-
containing protein-3 (TIM-3) in liver cancer cells. PD-1
and TIM-3 are proteins that help cancer cells evade the
immune system. By reducing the expression of these
proteins, propranolol can make liver cancer cells more
susceptible to attack by the immune system. It has also
48
been found that propranolol can increase the expression of
granzyme B and interferon-gamma (IFN-γ) in liver cancer
cells. Granzyme B is a protein that helps to kill cancer cells,
and IFN-γ is a cytokine that helps to activate the immune
Figure 1. Chemical structure of propranolol system. By increasing the expression of these proteins,

Volume 11 Issue 4 (2025) 22 doi: 10.36922/JCTR025080010