Vol 19, No 2 (2023)
Review paper
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Benefits of β-blockers in cancer treatment

Mohamad Arif1, Mardiah Suci Hardianti2, Nurina Tyagita3, Azizah Hikma Safitri3
Oncol Clin Pract 2023;19(2):90-100.

Abstract

Cancer is one of the leading causes of death in the world. Researchers keep attempting to develop therapy modalities to decrease the mortality and morbidity of cancer patients by trying to comprehend the effect of sympathetic nerves (through catecholamine and adrenergic receptors) in cancer development. Catecholamine activation in β-adrenergic receptors (β1-AR, β2-AR, and β3-AR) may influence cytokine and cancer immunity system, initiate tumorigenesis, stimulate tumor-associated macrophage and angiogenesis, influence tumor microenvironment, and facilitate cancer cell metastasis, leading to increased progressivity of cancer cells. β-blockers may inhibit catecholamine on β-AR and various types of paths needed for cancer cells to develop. β-blockers also stimulate cancer cell apoptosis, decrease pro-inflammatory mediators and growth factors of cancer cells. In addition, β-blockers also have benefits as supplementary cancer therapy, increase chemoradiotherapy sensitivity, decrease cardiotoxicity, and improve cancer cachexia. The benefits of β-blockers are expected to reduce morbidity and increase the survival rates of cancer patients. This review comprehensively assesses the benefit of β-blockers as a part of the complete management of cancer patients.

Review article

Oncology in Clinical Practice

DOI: 10.5603/OCP.2022.0016

Copyright © 2023 Via Medica

ISSN 2450–1654

e-ISSN 2450–6478

Benefits of b-blockers in cancer treatment

Mohamad Arif1Mardiah Suci Hardianti2Nurina Tyagita3Azizah Hikma Safitri3
1Division of Hematology and Medical Oncology, Department of Internal Medicine Science, Faculty of Medicine, Universitas Islam Sultan Agung (UNISSULA)/ Sultan Agung Islamic Hospital, Semarang, Indonesia
2Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr. Sardjito Hospital, Yogyakarta, Indonesia
3Department of Biochemistry, Faculty of Medicine, Universitas Islam Sultan Agung (UNISSULA), Semarang, Indonesia

Address for correspondence:

Azizah Hikma Safitri, S.Si, M.Si

Department of Biochemistry, Faculty of

Medicine, Universitas Islam Sultan Agung

(UNISSULA), Semarang Indonesia-50112

tel.: +62 24 6583584

e-mail: azizah.safitri@unissula.ac.id

Received: 16.08.2021 Accepted: 19.10.2021 Early publication date: 06.04.2022

ABSTRACT

Cancer is one of the leading causes of death in the world. Researchers keep attempting to develop therapy modalities to decrease the mortality and morbidity of cancer patients by trying to comprehend the effect of sympathetic nerves (through catecholamine and adrenergic receptors) in cancer development. Catecholamine activation in b-adrenergic receptors (b١-AR, b٢-AR, and b٣-AR) may influence cytokine and cancer immunity system, initiate tumorigenesis, stimulate tumor-associated macrophage and angiogenesis, influence tumor microenvironment, and facilitate cancer cell metastasis, leading to increased progressivity of cancer cells. b-blockers may inhibit catecholamine on b-AR and various types of paths needed for cancer cells to develop. b-blockers also stimulate cancer cell apoptosis, decrease pro-inflammatory mediators and growth factors of cancer cells. In addition, b-blockers also have benefits as supplementary cancer therapy, increase chemoradiotherapy sensitivity, decrease cardiotoxicity, and improve cancer cachexia. The benefits of b-blockers are expected to reduce morbidity and increase the survival rates of cancer patients. This review comprehensively assesses the benefit of b-blockers as a part of the complete management of cancer patients.

Key words: catecholamine, b-blockers, cancer, therapy

Oncol Clin Pract 2023; 19, 2: 90100

Introduction

Cancer is one of the leading causes of death in the world. Global Cancer Statistic estimated there were 19.3 million of new cases, and 10 million deaths of cancer found in 2020. Various therapy modalities have been developed to reduce cancer mortality and morbidity rates, however, the results are still not satisfactory [1]. Current research focuses on studying the role of sympathetic nerves (through catecholamine and adrenergic receptors) in cancer development [2].

The role of catecholamine and adrenaline in cancer progression is related to their receptors. Neurotransmitters of catecholamine epinephrine (EP) and norepinephrine (NE) are related to a-adrenergic receptor (a-AR) and b- adrenergic receptor (b-AR) [3]. b-AR consists of 3 types, b١-AR, b٢-AR, and b٣-AR. b-AR exists in almost all normal tissues of the human body. Interestingly, b-AR (especially b٢-AR) expression increases significantly on the surface of some types of primary cancer cells (most strongly in melanoma, breast, esophagus, pancreas) and metastasis cancer cells. Activation of b-AR by catecholamine modulates the progression and proliferation of tumor cells [4]. In addition, activation of b-AR regulates the cellular metabolic process, which is related to initiation and progressivity of cancer cells, including cell inflammation, tissue angiogenesis, cell apoptosis, cell communication and movement, repair of damaged DNA, cancer-related cellular immune response, and cell epithelial-mesenchymal transition [5].

Figure 1. Flow chart illustrating article selection

b-blockers are the adrenoceptor antagonist which inhibits the b-AR receptor. b-blockers are an inexpensive drug, available throughout most of the world, with a relatively good drug safety profile [6]. b-blockers decrease the effect of catecholamine in human body cells [7]. Inhibition of beta-AR blockers slows down the progressivity of cancer progressivity of cancer and increases the survival rate of cancer patients [8]. The other beneficial effect of b-blockers is to prevent chemotherapy’s side effects and increase the sensitivity of cancer cells to chemotherapy [9, 10]. The advantages of b-blockers as therapy in cancer management need to be studied further.

Methods

This literature review aimed to review recent developments and publications concerning the role of the b-blocker in cancer treatment. We reviewed all publications from the database of PubMed and Google Scholar published between 20162021 as illustrated in Figure 1. Older articles are included if they provide important information. First, we used the terms “catecholamine” AND “cancer or malignancy.” Then, we continued using the terms “beta blocker” AND “cancer or malignancy” AND “treatment or management.” We also searched for other specific keywords, such as “chemo-radiotherapy” OR “cardiotoxicity” OR “cancer cachexia” OR “survival.”

Results

Catecholamine influences cytokine and cancer immune system

Catecholamine released during chronic stress influences immune response [11]. Stimulation of catecholamine on b-AR causes macrophage polarization (Fig 2.) and cytokine production and gives rise to the development and progressivity of breast cancer [12].

Chronic activation of b-AR signal on mice suppresses the activity and number of natural killer cells (NK cell), increasing the risk of cancer cell metastasis [13]. Activation of the b-AR signal also increases the expression of the anti-apoptotic protein molecule (BAD, BCL-2, and MCP-1) on tumor cells. Norepinephrine activates the path of transforming growth factor b (TGF-b) in cancer cells and increases the capability of distant metastasis [11, 14]. Norepinephrine also increases the chemotaxis ability of breast cancer cells for distant metastasis mediated by chemokine [15].

Catecholamine stimulates polarization of macrophage M2

The activation of b-AR by catecholamine strongly stimulates macrophage to polarize into macrophage M2 (Fig. 2). Stimulation of b-AR can reverse M1-like macrophages into M2. Decreasing the content of catecholamine in the body may reduce the polarization of macrophage into M2. M2 exists in a large number around tumor cells along with growing new tiny blood vessels that support the life of tumor cells [12, 16].

Catecholamine triggers tumorigenesis

DNA damage may trigger tumor formation [17]. The direct effect of catecholamine on cancer cells is to promote tumorigenesis, tumor cells proliferation, anti-apoptotic, and promote metastasis through the DNA damage pathway [18, 19]. The effect of catecholamine on b2-AR increases the degradation of p53 and causes DNA damage. This process occurs through arrestin beta 1 (ARRB1) pathways, protein kinase A (PKA), and activation of proto-oncogene Src and Her2 [20, 21].

Chronic activation of adrenoceptor by G-coupled protein may induce normal cells to have malignant transformation [22]. Prolonged exposure of norepinephrine and epinephrine to NIH3T3 cells (experiment mouse fibroblast cell) and murine 3T3 cells increases DNA damage, cell proliferation rate, and tumor formation. This shows that the normal cellular genes act as a proto-oncogene, which is the initial stage of tumor formation [20, 23]. Activation of PKA by b2-AR receptor will result in reactive oxygen species (ROS) which damages DNA. This study demonstrates that catecholamine induces DNA damage in normal cells and triggers cancer cell development [21].

Figure 2. Catecholamine action towards cancer progressiveness; TGFb tumor growth factor beta; NK cell natural killer cell; ARRB arrestin beta 1; PKA protein kinase A; VPF vascular permeability factor; VEGF vascular endothelial growth factor; CAF cancer-associated fibroblasts; hTERT human telomerase reverse transcriptase; MMP matrix metalloproteinase

Other evidence states that norepinephrine induces phosphorylation of voltage-dependent calcium channels (VDCC) L-type through the b-adrenergic receptor (b-AR) -PKA pathway. VDCC triggers calcium mobilization, inducing activation of IGF-1R through exocytosis of insulin-like growth factor (IGF2). Mice expressing lung-specific IGF-1R show faster development of lung tumors [24]. Norepinephrine also stimulates the expression of human telomerase reverse transcriptase (hTERT), which initiates cancer formation through epithelial-mesenchymal transition (EMT) [25].

Catecholamine influences angiogenesis

b-AR (b1-AR, b2-AR, and b3-AR) subtypes are expressed on the blood vessel of tumor tissue [26]. b2-AR activation by catecholamine on tumor cells increases the formation of proangiogenic factors [27]. Norepinephrine activates cAMP-protein kinase A (PKA), increases vascular permeability factor/vascular endothelial growth factor-A (VPF/VEGF) synthesis, and expression of matrix metalloprotease 2 (MMP 2) and MMP 9 are increased [28]. b2-AR also stimulates activation of Epac1 (exchange factor directly activated by cAMP1) and PKA that will increase vascular endothelial growth factor (VEGF) [29].

Activation of noradrenaline on b2-AR of endothelial cells is important to start the angiogenic process that triggers tumor cell growth. The removal of b2-AR on endothelial cells inhibits metabolic changes needed by the cancer cell angiogenesis process. Oxidative phosphorylation and formation of mitochondrial cytochrome C are also increased, and thus they inhibit angiogenesis and cancer cell growth [30].

Catecholamine influences tumor microenvironment

Neurotransmitter catecholamine of sympathetic nervous system modulates bone marrow cell microenvironment, thus increasing cancer cell progressivity [31]. Norepinephrine, through b3-AR, increases cancer-associated fibroblasts (CAF) activation, maintains pro-inflammatory cytokine secretion, which is important to maintain the tumor microenvironment. b3-AR also stimulates the mobilization of precursor cells (mesenchymal stem cells and endothelial precursor cells) of bone marrow into tumor cells. The precursor cells become adult CAF, which supports the inflammatory and angiogenesis processes of tumor cells [32]. b3-AR activation causes cancer cells to be more sensitive to environmental stimulation, namely hypoxia, nutritional availability, CAF count, and cancer-associated macrophages (CAM). The cascade described is like a vicious circle that will repair the microenvironment, inflammatory process, and cancer cell angiogenesis [33, 34].

Catecholamine also influences stromal cell-derived factor 1 (CXCL12) that serves to change the hematopoietic stem and progenitor cells (HSPCs) and bone marrow homing process. The microenvironment change is preferred as a place for cancer cell metastasis [35].

Catecholamine’s role in cancer pathogenesis, as stated earlier, is that it influences cancer growth and development. Catecholamine action towards cancer progressiveness is presented in Figure 2. Inhibition of catecholamine receptors is also deemed to influence cancer progressivity. Thus, b-blockers, as the agonist of b-AR adrenoceptor, can be used to inhibit cancer development.

Effect of b-blockers on cancer

Denervation of tumor tissue stops catecholamine flow on b-AR in cancer cells, inhibiting the growth and spread of cancer cells. Administrating b-blockers also causes denervation of tumor tissue and inhibits the growth and spread of cancer cells [36, 37]. Catecholamines influence cancer development through their activity at b adrenergic receptors (b-AR 1, b-AR 2, and b-AR 3) [38]. In this article, we divide b-blockers (traditionally) into non-selective b-blockers and selective b-blockers. We used propranolol, carvedilol, and nebivolol as sample drugs in this study because they are representative of each type of b-blocker, and they are widely used in clinical practice and appear in our study search results. Propranolol represents an older non- -selective b-blocker. Carvedilol represents a newer non-selective b-blocker. Nebivolol represents a selective b-blocker.

In this article, we divide the effect of b-blockers on cancer into experimental (in vitro) and clinical studies.

Effects of non-selective b-blockers in experimental cancer studies

Propranolol

The propranolol inhibition on b-AR is not selectively limited. This is beneficial since propranolol can inhibit catecholamine effects in every adrenergic receptor (b1-3AR) expressed by various cancer cells [4, 5].

Propranolol administration in an in-vitro study to some cancer types shows an inhibitory effect in various types of metabolic paths of cancer cells. Propranolol stimulates activation of poly (ADP-ribose) polymerase (enzyme serving to repair DNA, genome stability, and cell apoptosis) in liver cancer. Propranolol stimulates liver cancer cell apoptosis by influencing the expression of enzyme caspase-3 (the enzyme which disturbs the cell cycle until ceasing in phase S) [39]. Administration of propranolol to squamous cell carcinoma, induced by norepinephrine, decreases the cancer migration and invasion ability [40].

Melanoma patients present a good response to propranolol treatment [41, 42]. Propranolol decreases the level of VEGF, which plays a role in angiogenesis in melanoma cases. Propranolol also stimulates melanoma cell apoptosis by inducing phase G0/G1/S through the PKB/MAPK (protein kinase B/mitogen-activated protein kinase) pathway [43]. Ovary cancer cell apoptosis is stimulated by propranolol through inhibiting the cell life cycle at phase G2/M. The protein content of beclin-1 and p62 that stimulates the process of autophagy of ovary cancer cells is also increased by propranolol [44].

The administration of propranolol in in-vitro research of colorectal cancer cells decreases the level of Hypoxia-Inducible Factor1 a (HIF1a) and carbonic anhydrase IX (CA-IX). CA-IX is a protein that repairs the microenvironment of cancer cells and improves cancer cells for distant metastasis. Propranolol reduces the amount of protein involved in oxidative phosphorylation, which may potentially reduce the risk of distant metastasis in colorectal cancer cells [45].

Propranolol can process immunomodulatory cellular immune responses related to cancer. Propranolol increases IL-2, IL-4, IL-12, IL-17, and IFN-g cytokines that can suppress breast cancer in experimental studies on animals [46]. Propranolol increases the number of CD 8+ cells and the expression of GzmB/IFN-g/T-bet on CD 8+ cells in colon cancer tissue of experimental mice [47].

Carvedilol

Research on carvedilol as cancer therapy until recently has remained in vitro. Skin cancer model cells, JB6P+, show high expression of b2-AR. The administration of carvedilol may inhibit epidermal growth factor (EGF) and activator protein (AP1) needed by JB6P+ cells to transform into malignant cells [48]. Carvedilol reduces anti-inflammatory activity by attenuating UV-induced AP-1 and NF-kB activity. It may inhibit the malignant transformation of skin cells because of exposure to ultraviolet light [49, 50].

Ductal carcinoma by exposure to strong carcinogen benzo(a)pyrene can be prevented by carvedilol through inhibition of ROS production which stimulates activation of the PI3K/AKT signal pathway (important signal of excessive cell growth) [51].

Effects of selective b-blockers in experimental cancer studies

Nebivolol

Research on selective b-blockers in inhibiting cancer progression in vitro is still very limited. In our search, nebivolol was a selective b-blocker that was frequently used in studies (though it is still rare). Nebivolol is a selective inhibitor of b1-AR and has a good effect on certain types of cancer. Nebivolol inhibits the use of glucose and palmitate in mitochondrial respiration of colorectal cancer, breast cancer, lung cancer, and ovary cancer cells. The utilization of inhibited glucose causes cancer cells not to produce ATP needed for cancer cell development [52]. Nebivolol downregulates VEGF2 receptor expression, needed in endothelial cell proliferation, inhibiting the cancer cell angiogenesis process. The life cycle of cancer cells is stopped by nebivolol by preventing activation of extracellular signal-regulated kinase (ERK) participating in cell cycle phase S [52]. In oral squamous cell carcinoma, nebivolol activates the endoplasmic reticulum (ER) stress signaling pathway by increasing the expression of inducible nitric oxide synthase. ER stress triggers mitochondrial dysfunction and cell growth arrest [53]. Only a few research studies have been conducted related to selective b-blockers on cancer cases since the inhibition is specific only to b1-AR. Summaries of b-blockers’ benefits in inhibiting cancer progression are presented in Table 1.

Effects of non-selective b-blockers in clinical cancer studies

Propranolol

Propranolol is useful and shows good results in patients with various types of breast cancer. Propranolol administered to early-stage breast cancer patients, downregulates the expression of protein pro-proliferative Ki-67. Phosphorylation of mediator regulating splitting of cancer cells (p44/42 MAPK, p38 MAPK, JNK, and CREB) lower, while phosphorylation of mediator stimulating cancer cell apoptosis (AKT, p53, and GSK3b) increases [54].

Propranolol administered as adjuvant therapy to late-stage breast cancer patients (stage 3 or higher) downregulates the expression of protein pro-proliferative Ki-67 and protein pro-survival Bcl-2 and increases the expression of protein pro-apoptotic p53. Propranolol is useful to deal with local and far-spread breast cancer cells [55].

The use of propranolol before diagnosis reduces the risk of cancer stage progression compared to patients without a propranolol use history. The breast cancer-specific mortality level also decreases significantly for patients who use propranolol [56]. Propranolol administration 7 days before breast cancer operation, reduces the biomarker of pro-metastatic inflammation (Activator protein-1, Snail/Slug, NF-KB/Rel) [57]. Meanwhile, propranolol administration to triple-negative breast cancer patients increases recurrence-free survival and reduces metastasis risk. Progression-free survival of HER2-negative breast cancer patients in the late stage is better with propranolol administration. Propranolol also improves the sensitivity to trastuzumab therapy for HER2-positive breast cancer patients [58].

Propranolol administration in combination with etodolac perioperative (20 days) improves colorectal cancer marking molecules, covering reduction of epithelial to mesenchymal transition, tumor-infiltrating CD14+ monocytes, and CD19+ B cells, and increases the number of tumor natural killer cells CD56+ [59]. Propranolol prolongs time-to-discontinuation of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and improves the overall survival of lung adenocarcinoma patients receiving first-line EGFR-TKIs therapy [60]. Propranolol also improves the overall survival of unresectable hepatocellular carcinoma patients [61].

Carvedilol

In a population-based study, long-term use of carvedilol has been shown to reduce the risk of gastric and lung cancer [62]. Nonselective b-blockers (including carvedilol) reduce the incidence of hepatocellular carcinoma in patients with liver cirrhosis [63]. Carvedilol also blocks neural regulation to reduce cancer-specific mortality in breast cancer [64].

Effects of selective b-blockers in clinical cancer studies

Our search shows that clinical studies of nebivolol are still limited. The benefits of selective b-blockers remain in the area of cardiotoxicity induced by chemoradiation therapy (as mentioned in Table 2).

b-blocker administration does not only affect cancer progressivity in clinical cancer studies but also serves as an adjunctive for conservative clinical cancer therapy.

b-blockers increase the sensitivity of cancer cells to chemo-radiotherapy

Chemo-radiotherapy is the modality commonly used in cancer patient treatment. Stimulation of catecholamine increases cancer cell progressivity and may reduce the effect of chemotherapy drugs, such as doxorubicin, on cancer cells. Inhibition of doxorubicin’s efficacy occurs through increasing expression of silent information regulator1 (Sirt-1) by catecholamine stimulation [10].

Administration of b-blockers increases the sensitivity of lung cancer cells to radiotherapy and drug cisplatin. Propranolol in combination with radiotherapy or cisplatin reduces the expression of phosphoprotein kinase A(p-PKA) that inhibits the survival of the clonogenic cells of lung adenocarcinoma compared to radiotherapy or cisplatin only [65]. The administration of propranolol to sarcoma increases the sensitivity to doxorubicin by changing drug metabolism in intracellular lysosomes. Propranolol inhibits the pump that releases doxorubicin to extracellular, increasing the level of intracellular doxorubicin and the ability of doxorubicin to damage the DNA of cancer cells [66]. Propranolol also increases the sensitivity to doxorubicin in myeloid leukemia cells [67].

Table 2. Summaries of b-blockers benefit in clinical cancer study (in vivo study)

Ref.

Drugs

Type of cancer

Mechanism

Outcome

[54]

Propranolol

Early-stage breast cancer

Øprotein pro-proliferative Ki-67 ØPhosphorylation of mediator regulating splitting of cancer cells (p44/42 MAPK, p38 MAPK, JNK, and CREB) phosphorylation of mediator stimulating cancer cell apoptosis (AKT, p53, and GSK3b)

Reduces tumor proliferative index

[55]

Propranolol

Late-stage breast cancer

Øprotein pro-proliferative Ki-67 Øprotein pro-survival Bcl-2 expression of protein pro-apoptotic p53

Øcancer cell cycle progression cell apoptotic

[56, 58]

Propranolol

Breast cancer

Ømetastasis development

Øtumor recurrence

disease-free interval

[59]

Propranolol with etodolac

Colorectal

Øepithelial to mesenchymal transition Øtumor-infiltrating CD14+ and CD19+ B cells, tumor natural killer cells CD56+

Improve colorectal cancer marking molecules

[60]

Propranolol

Lung adenocarcinoma

time-to-discontinuation (EGFR-TKIs) and overall survival of lung adenocarcinoma

[62]

Carvedilol

Gastric and lung cancer

Ørisk of gastric and lung cancer

[63]

Nonselective b-blockers (including carvedilol)

HCC

Øincidence of HCC in liver cirrhosis

[64]

Carvedilol

Breast cancer

Blocks neural regulation

Øcancer-specific mortality ØTumor growth

HCC — hepatocellular carcinoma

Propranolol administered to experimental mice, increases the sensitivity of stomach cancer cells to radiotherapy. Propranolol reduces the expression of NF-kB, EGFR, VEGF, COX-2 in stomach cancer cells, becoming more sensitive to radiotherapy [68]. Propranolol and carvedilol can significantly reduce the number of fractions of a dog’s osteosarcoma cells after 3 Gy radiation [69].

b-blockers increase the effectiveness of immune checkpoint inhibitors

b-blockers also serve to increase the effectiveness of immunotherapy. CD8+ cytotoxic T lymphocytes (CTLs) are one target of treatment through immune checkpoint inhibitors (ICI). The lymphocyte cells kill cancer cells that represent major histocompatibility complex molecules MHC class 1 [70]. On the other hand, activation of b-AR in CD8+ CTLs cells reduces cells’ ability to kill cancer cells, reducing interferon proliferation and production ability. The administration of b-blockers increases CD8+ CTLs count [71]. Non-small cell lung cancer patients receiving ICI therapy in combination with b-blockers show improved progression-free survival [72].

Table 3. Summaries of b-blockers improve cancer survival

Ref.

Drugs

Type of cancer

Type of study

Outcome

[93]

b-blocker

Systematic review and meta-analysis

Øall-cause mortality

[94]

b-blocker

Meta-analysis

overall survival disease-free survival

[95]

b-blocker

Ovary cancer, pancreas cancer, breast cancer, and melanoma

Meta-analysis

cancer-specific survival

[96]

b-blocker

Breast cancer

Retrospective

disease-free interval

[61]

Propranolol

Unresectable HCC

Population-based study

Ømortality risk

HCC — hepatocellular carcinoma

b-blockers prevent cardiotoxic effects of chemo-radiotherapy

Anthracycline is a chemotherapy drug with a cardiotoxic effect. Anthracycline causes increased reactive oxygen species (ROS) accumulated in cardiac muscle mitochondria [73]. b-blockers (carvedilol and nebivolol) serve as an antioxidant that reduces oxidative stress in cardiac muscle, preventing damage to the heart because of anthracycline [74, 75].

Carvedilol prevents reduction of left ventricular ejection fraction (LVEF), prevents diastolic dysfunction, and cardiac remodeling. Carvedilol reduces markers of heart damage in patients receiving anthracycline or trastuzumab therapy [76–79].

Nebivolol prevents reduction of myocardial velocities and deformation of the ventricular muscle structure of breast cancer patients receiving doxorubicin therapy [80]. This protective effect is caused by its ability to modulate caspase-3, e/i NOS, and TNF alpha that prevents apoptosis in cardiac muscle [81]. Nebivolol also increases nitrite oxide content serving as an antioxidant [82].

Radiotherapy in the breast area can also cause cardiotoxicity. This damage includes cardiomyopathy, acceleration of formation of atherosclerosis, fibrosis pericardial valve and tissue, and cardiac conduction disorder [83]. These damages can generally be treated using b-blockers [84, 85].

b-blockers prevent cancer cachexia

There is currently no specific therapy for cancer cachexia. One modality proposed as cancer cachexia therapy is to administer b-blockers [86, 87]. Cancer cachexia, besides extremely reducing muscle mass, also causes a reduction of cardiac muscle mass (cardiac cachexia). Cardiac cachexia makes it more difficult to treat the effect of chemotherapy-induced cardiotoxicity [88, 89]. b-blockers (particularly selective b1-blockers) prevent worsening cardiac cachexia [90, 91]. Espindolol increases body weight and body fat proportion in colorectal and lung cancer patients. The effect of Espindolol is related to its ability to reduce metabolism (nonselective inhibition on b-AR), reduce fatigue and thermogenesis (as an agonist of central 5-HT1a receptors), and pro-anabolic effect (as a partial agonist of b-2 receptors) [92].

b-blockers and cancer survival

Our review shows that b-blockers, especially nonselective b-blockers, are beneficial in improving overall survival by preventing cancer progression and as adjunctive therapy to conventional cancer therapy (as listed in Table 3). However, studies are not consistent in showing that b-blockers have improved overall survival (OS).

Meta-analysis research shows that b-blockers reduce the hazard ratio of all-cause mortality of cancer patients [93] and increase the overall survival and disease-free survival of cancer patients (particularly ovary cancer, pancreas cancer, breast cancer, and melanoma) [94, 95]. Administration of b-blockers to breast cancer patients significantly reduces metastasis occurrence, cancer recurrence, and longer disease-free intervals [96].

The research conducted by Na et al. states, conversely, that there is no evidence showing the correlation between the use of b-blocker and overall survival, all-cause mortality, disease-free survival, progression-free survival, and recurrence-free survival for cancer patients. The varied results are caused by different study designs, different drug working methods, type and stages of cancer, too heterogeneous sample population, and time of b-blocker administration [93, 97]. The other reasons are due to the progression of cancer through various molecular pathways, not only through the catecholamine pathway [98, 99]. In addition, many exogen factors affect cancer mortality/overall survival (i.e depression, economy, delayed treatment, surgery, nutrition) [100]. Another confounder that may influence the difference in the result of research on b-blockers in the survival of cancer patients is immortal time bias (ITB). ITB may cause the result of survival-related research to seem better. Meta-analysis and systematic review researches excluding ITB influence in their studies on the influence of b-blockers on cancer survival show insignificant results [101, 102].

Conclusion

Administrating b-blockers inhibits catecholamine activation through b adrenoceptors (b1-AR, b2-AR, and b3-AR), so that cancer cell formation, progression, and metastasis are inhibited. b-blockers are also useful as adjunctive therapy to prevent cancer cachexia, chemoradiotherapy-related cardiotoxicity, and can increase the sensitivity to immune checkpoint inhibitors and chemoradiotherapy. The benefits of b-blockers will be stronger when they are applied to cancers that strongly express b adrenergic receptors (e.g. melanoma, breast cancer). Non-selective b-blockers are superior to selective b-blockers since they block all three types of b adrenergic receptors.

Conflict of interest

Authors declare no conflict of interest.

References

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209249, doi: 10.3322/caac.21660, indexed in Pubmed: 33538338.
  2. Coelho M, Soares-Silva C, Brandão D, et al. b-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives. J Cancer Res Clin Oncol. 2017; 143(2): 275291, doi: 10.1007/s00432-016-2278-1, indexed in Pubmed: 27709364.
  3. Wehrwein EA, Orer HS, Barman SM. Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System. Compr Physiol. 2016; 6(3): 12391278, doi: 10.1002/cphy.c150037, indexed in Pubmed: 27347892.
  4. Rains SL, Amaya CN, Bryan BA. Beta-adrenergic receptors are expressed across diverse cancers. Oncoscience. 2017; 4(7-8): 95105, doi: 10.18632/oncoscience.357, indexed in Pubmed: 28966942.
  5. Cole SW, Sood AK. Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res. 2012; 18(5): 12011206, doi: 10.1158/1078-0432.CCR-11-0641, indexed in Pubmed: 22186256.
  6. do Vale GT, Ceron CS, Gonzaga NA, et al. Three Generations of b-blockers: History, Class Differences and Clinical Applicability. Curr Hypertens Rev. 2019; 15(1): 2231, doi: 10.2174/1573402114666180918102735, indexed in Pubmed: 30227820.
  7. Berg T. b1-Blockers Lower Norepinephrine Release by Inhibiting Presynaptic, Facilitating b1-Adrenoceptors in Normotensive and Hypertensive Rats. Front Neurol. 2014; 5: 51, doi: 10.3389/fneur.2014.00051, indexed in Pubmed: 24795691.
  8. Peixoto R, Pereira Md, Oliveira M. Beta-Blockers and Cancer: Where Are We? Pharmaceuticals (Basel). 2020; 13(6), doi: 10.3390/ph13060105, indexed in Pubmed: 32466499.
  9. Gujral DM, Lloyd G, Bhattacharyya S. Effect of prophylactic betablocker or ACE inhibitor on cardiac dysfunction & heart failure during anthracycline chemotherapy ± trastuzumab. Breast. 2018; 37: 6471, doi: 10.1016/j.breast.2017.10.010, indexed in Pubmed: 29101824.
  10. Chen H, Zhang W, Cheng X, et al. b2-AR activation induces chemoresistance by modulating p53 acetylation through upregulating Sirt1 in cervical cancer cells. Cancer Science. 2017; 108(7): 13101317, doi: 10.1111/cas.13275.
  11. Qiao G, Chen M, Bucsek MJ, et al. Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response. Front Immunol. 2018; 9: 164, doi: 10.3389/fimmu.2018.00164, indexed in Pubmed: 29479349.
  12. Qin Jf, Jin Fj, Li N, et al. Adrenergic receptor b2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep. 2015; 48(5): 295300, doi: 10.5483/bmbrep.2015.48.5.008, indexed in Pubmed: 25748171.
  13. Shakhar G, Ben-eliyahu S. In Vivo Beta Adrenergic Stimulation Suppresses Natural Killer Activity and Compromises Resistance to Tumor Metastasis in Rats. J Immunol. 1998; 160(7): 32513258.
  14. Pu J, Zhang X, Luo H, et al. Adrenaline promotes epithelial-to-mesenchymal transition via HuR-TGFb regulatory axis in pancreatic cancer cells and the implication in cancer prognosis. Biochem Biophys Res Commun. 2017; 493(3): 12731279, doi: 10.1016/j.bbrc.2017.09.146, indexed in Pubmed: 28965949.
  15. Drell TL, Joseph J, Lang K, et al. Effects of Neurotransmitters on the Chemokinesis and Chemotaxis of MDA-MB-468 Human Breast Carcinoma Cells. Breast Cancer Research and Treatment. 2003; 80(1): 6370, doi: 10.1023/a:1024491219366.
  16. Xia Y, Wei Ye, Li ZY, et al. Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages. Brain Behav Immun. 2019; 81: 111121, doi: 10.1016/j.bbi.2019.06.004, indexed in Pubmed: 31176001.
  17. Srinivas US, Tan BWQ, Vellayappan BA, et al. ROS and the DNA damage response in cancer. Redox Biol. 2019; 25: 101084, doi: 10.1016/j.redox.2018.101084, indexed in Pubmed: 30612957.
  18. Dai S, Mo Y, Wang Y, et al. Chronic Stress Promotes Cancer Development. Front Oncol. 2020; 10: 1492, doi: 10.3389/fonc.2020.01492, indexed in Pubmed: 32974180.
  19. Lamboy-Caraballo R, Ortiz-Sanchez C, Acevedo-Santiago A, et al. Norepinephrine-Induced DNA Damage in Ovarian Cancer Cells. Int J Mol Sci. 2020; 21(6), doi: 10.3390/ijms21062250, indexed in Pubmed: 32213975.
  20. Flint MS, Baum A, Episcopo B, et al. Chronic exposure to stress hormones promotes transformation and tumorigenicity of 3T3 mouse fibroblasts. Stress. 2013; 16(1): 114121, doi: 10.3109/10253890.2012.686075, indexed in Pubmed: 22506837.
  21. Hara MR, Kovacs JJ, Whalen EJ, et al. A stress response pathway regulates DNA damage through b2-adrenoreceptors and b-arrestin-1. Nature. 2011; 477(7364): 349353, doi: 10.1038/nature10368, indexed in Pubmed: 21857681.
  22. Eng JWL, Kokolus KM, Reed CB, et al. A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol Immunother. 2014; 63(11): 11151128, doi: 10.1007/s00262-014-1617-9, indexed in Pubmed: 25307152.
  23. Allen LF, Lefkowitz RJ, Caron MG, et al. G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha 1B-adrenergic receptor enhances mitogenesis and tumorigenicity. Proc Natl Acad Sci U S A. 1991; 88(24): 1135411358, doi: 10.1073/pnas.88.24.11354, indexed in Pubmed: 1662393.
  24. Jang HJ, Boo HJ, Lee HoJ, et al. Chronic Stress Facilitates Lung Tumorigenesis by Promoting Exocytosis of IGF2 in Lung Epithelial Cells. Cancer Res. 2016; 76(22): 66076619, doi: 10.1158/0008-5472.CAN-16-0990, indexed in Pubmed: 27651310.
  25. Choi MJ, Cho KH, Lee S, et al. hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness. Oncogene. 2015; 34(26): 34023412, doi: 10.1038/onc.2014.270, indexed in Pubmed: 25151968.
  26. Chisholm KM, Chang KW, Truong MT, et al. b-Adrenergic receptor expression in vascular tumors. Mod Pathol. 2012; 25(11): 14461451, doi: 10.1038/modpathol.2012.108, indexed in Pubmed: 22743651.
  27. Chakroborty D, Sarkar C, Basu B, et al. Catecholamines regulate tumor angiogenesis. Cancer Res. 2009; 69(9): 37273730, doi: 10.1158/0008-5472.CAN-08-4289, indexed in Pubmed: 19383906.
  28. Thaker PH, Han LY, Kamat AA, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006; 12(8): 939944, doi: 10.1038/nm1447, indexed in Pubmed: 16862152.
  29. Garg J, Feng YX, Jansen SR, et al. Catecholamines facilitate VEGF-dependent angiogenesis via b2-adrenoceptor-induced Epac1 and PKA activation. Oncotarget. 2017; 8(27): 4473244748, doi: 10.18632/oncotarget.17267, indexed in Pubmed: 28512254.
  30. Zahalka AH, et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science (80-. ). 2017; 358: 321326.
  31. Wang W, Li L, Chen N, et al. Nerves in the Tumor Microenvironment: Origin and Effects. Front Cell Dev Biol. 2020; 8: 601738, doi: 10.3389/fcell.2020.601738, indexed in Pubmed: 33392191.
  32. Santi A, Kugeratski FG, Zanivan S. Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics. 2018; 18(5-6): e1700167, doi: 10.1002/pmic.201700167, indexed in Pubmed: 29280568.
  33. Calvani M, Pelon F, Comito G, et al. Norepinephrine promotes tumor microenvironment reactivity through b3-adrenoreceptors during melanoma progression. Oncotarget. 2015; 6(7): 46154632, doi: 10.18632/oncotarget.2652, indexed in Pubmed: 25474135.
  34. Chiarugi P, Filippi L. b3-adrenoreceptor and tumor microenvironment: a new hub. Oncoimmunology. 2015; 4(11): e1026532, doi: 10.1080/2162402X.2015.1026532, indexed in Pubmed: 26504670.
  35. Hanns P, Paczulla AM, Medinger M, et al. Stress and catecholamines modulate the bone marrow microenvironment to promote tumorigenesis. Cell Stress. 2019; 3(7): 221235, doi: 10.15698/cst2019.07.192, indexed in Pubmed: 31338489.
  36. Boilly B, Faulkner S, Jobling P, et al. Nerve Dependence: From Regeneration to Cancer. Cancer Cell. 2017; 31(3): 342354, doi: 10.1016/j.ccell.2017.02.005, indexed in Pubmed: 28292437.
  37. Hondermarck H, Jobling P. The Sympathetic Nervous System Drives Tumor Angiogenesis. Trends Cancer. 2018; 4(2): 9394, doi: 10.1016/j.trecan.2017.11.008, indexed in Pubmed: 29458965.
  38. Mravec B, Horvathova L, Hunakova L. Neurobiology of Cancer: the Role of b-Adrenergic Receptor Signaling in Various Tumor Environments. Int J Mol Sci. 2020; 21(21), doi: 10.3390/ijms21217958, indexed in Pubmed: 33114769.
  39. Wang F, Liu H, Wang F, et al. Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells. Mol Med Rep. 2018; 17(4): 52135221, doi: 10.3892/mmr.2018.8476, indexed in Pubmed: 29393410.
  40. Bravo-Calderón DM, Assao A, Garcia NG, et al. Beta adrenergic receptor activation inhibits oral cancer migration and invasiveness. Arch Oral Biol. 2020; 118: 104865, doi: 10.1016/j.archoralbio.2020.104865, indexed in Pubmed: 32801034.
  41. Vojvodic A, Vojvodic P, Vlaskovic-Jovicevic T, et al. Beta Blockers and Melanoma. Open Access Macedonian Journal of Medical Sciences. 2019; 7(18): 31103112, doi: 10.3889/oamjms.2019.782.
  42. De Giorgi V, Geppetti P, Lupi C, et al. The Role of b-Blockers in Melanoma. J Neuroimmune Pharmacol. 2020; 15(1): 1726, doi: 10.1007/s11481-019-09876-9, indexed in Pubmed: 1482435.
  43. Bustamante P, Miyamoto D, Goyeneche A, et al. Beta-blockers exert potent anti-tumor effects in cutaneous and uveal melanoma. Cancer Medicine. 2019; 8(17): 72657277, doi: 10.1002/cam4.2594.
  44. Zhao S, Fan S, Shi Y, et al. Propranolol induced apoptosis and autophagy the ROS/JNK signaling pathway in Human Ovarian Cancer. J Cancer. 2020; 11(20): 59005910, doi: 10.7150/jca.46556, indexed in Pubmed: 32922532.
  45. Barathova M, Grossmannova K, Belvoncikova P, et al. Impairment of Hypoxia-Induced CA IX by Beta-Blocker Propranolol-Impact on Progression and Metastatic Potential of Colorectal Cancer Cells. Int J Mol Sci. 2020; 21(22), doi: 10.3390/ijms21228760, indexed in Pubmed: 33228233.
  46. Ashrafi S, Shapouri R, Shirkhani A, et al. Anti-tumor effects of propranolol: Adjuvant activity on a transplanted murine breast cancer model. Biomed Pharmacother. 2018; 104: 4551, doi: 10.1016/j.biopha.2018.05.002, indexed in Pubmed: 29758415.
  47. Liao P, Song K, Zhu Z, et al. Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8 T Cells and Inhibiting Tumor AKT/MAPK Pathway. Clin Pharmacol Ther. 2020; 108(3): 606615, doi: 10.1002/cpt.1894, indexed in Pubmed: 32418204.
  48. Chang A, Yeung S, Thakkar A, et al. Prevention of skin carcinogenesis by the b-blocker carvedilol. Cancer Prev Res (Phila). 2015; 8(1): 2736, doi: 10.1158/1940-6207.CAPR-14-0193, indexed in Pubmed: 25367979.
  49. Huang KM, Liang S, Yeung S, et al. Topically Applied Carvedilol Attenuates Solar Ultraviolet Radiation Induced Skin Carcinogenesis. Cancer Prev Res (Phila). 2017; 10(10): 598606, doi: 10.1158/1940-6207.CAPR-17-0132, indexed in Pubmed: 28912118.
  50. Chen M, Shamim MdA, Shahid A, et al. Topical Delivery of Carvedilol Loaded Nano-Transfersomes for Skin Cancer Chemoprevention. Pharmaceutics. 2020; 12(12), doi: 10.3390/pharmaceutics12121151, indexed in Pubmed: 33260886.
  51. Ma Z, Liu X, Zhang Q, et al. Carvedilol suppresses malignant proliferation of mammary epithelial cells through inhibition of the ROS-mediated PI3K/AKT signaling pathway. Oncol Rep. 2019; 41(2): 811818, doi: 10.3892/or.2018.6873, indexed in Pubmed: 30483797.
  52. Nuevo-Tapioles C, Santacatterina F, Stamatakis K, et al. Coordinate b-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth. Nat Commun. 2020; 11(1): 3606, doi: 10.1038/s41467-020-17384-1, indexed in Pubmed: 32681016.
  53. Chen Q, Jiang H, Wang Z, et al. Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth Endoplasmic Reticulum Stress and Mitochondria Dysfunction. Front Pharmacol. 2021; 12: 691998, doi: 10.3389/fphar.2021.691998, indexed in Pubmed: 34456721.
  54. Montoya A, Amaya CN, Belmont A, et al. Use of non-selective b-blockers is associated with decreased tumor proliferative indices in early stage breast cancer. Oncotarget. 2017; 8(4): 64466460, doi: 10.18632/oncotarget.14119, indexed in Pubmed: 28031536.
  55. Montoya A, Varela-Ramirez A, Dickerson E, et al. The beta adrenergic receptor antagonist propranolol alters mitogenic and apoptotic signaling in late stage breast cancer. Biomed J. 2019; 42(3): 155165, doi: 10.1016/j.bj.2019.02.003, indexed in Pubmed: 31466709.
  56. Barron TI, Connolly RM, Sharp L, et al. Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol. 2011; 29(19): 26352644, doi: 10.1200/JCO.2010.33.5422, indexed in Pubmed: 21632503.
  57. Hiller J, Cole S, Crone E, et al. Preoperative b-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial. Clinical Cancer Research. 2019; 26(8): 18031811, doi: 10.1158/1078-0432.ccr-19-2641.
  58. Pantziarka P, Bryan BA, Crispino S, et al. Propranolol and breast cancer-a work in progress. Ecancermedicalscience. 2018; 12: ed82, doi: 10.3332/ecancer.2018.ed82, indexed in Pubmed: 30034523.
  59. Haldar R, Ricon-Becker I, Radin A, et al. Perioperative COX2 and b-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial. Cancer. 2020; 126(17): 39914001, doi: 10.1002/cncr.32950, indexed in Pubmed: 32533792.
  60. Chang CH, Lee CH, Ko JC, et al. Effect of b-Blocker in Treatment-Naïve Patients With Advanced Lung Adenocarcinoma Receiving First-Generation EGFR-TKIs. Front Oncol. 2020; 10: 583529, doi: 10.3389/fonc.2020.583529, indexed in Pubmed: 33194721.
  61. Chang PY, Chung CH, Chang WC, et al. The effect of propranolol on the prognosis of hepatocellular carcinoma: A nationwide population-based study. PLoS One. 2019; 14(5): e0216828, doi: 10.1371/journal.pone.0216828, indexed in Pubmed: 31125347.
  62. 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: 913, doi: 10.1016/j.ijcard.2015.02.015, indexed in Pubmed: 25705003.
  63. Wijarnpreecha K, Li F, Xiang Y, et al. Nonselective beta-blockers are associated with a lower risk of hepatocellular carcinoma among cirrhotic patients in the United States. Aliment Pharmacol Ther. 2021; 54(4): 481492, doi: 10.1111/apt.16490, indexed in Pubmed: 34224163.
  64. Gillis RD, Botteri E, Chang A, et al. Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients. Eur J Cancer. 2021; 147: 106116, doi: 10.1016/j.ejca.2021.01.029, indexed in Pubmed: 33639323.
  65. Chaudhary KR, Yan SX, Heilbroner SP, et al. Effects of b-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. J Clin Med. 2019; 8(5), doi: 10.3390/jcm8050575, indexed in Pubmed: 31035526.
  66. Saha J, Kim JH, Amaya CN, et al. Propranolol Sensitizes Vascular Sarcoma Cells to Doxorubicin by Altering Lysosomal Drug Sequestration and Drug Efflux. Front Oncol. 2020; 10: 614288, doi: 10.3389/fonc.2020.614288, indexed in Pubmed: 33598432.
  67. Calvani M, Dabraio A, Bruno G, et al. b3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance. Int J Mol Sci. 2020; 21(12), doi: 10.3390/ijms21124210, indexed in Pubmed: 32545695.
  68. Liao X, Chaudhary P, Qiu G, et al. The role of propranolol as a radiosensitizer in gastric cancer treatment. Drug Des Devel Ther. 2018; 12: 639645, doi: 10.2147/DDDT.S160865, indexed in Pubmed: 29636598.
  69. Duckett MM, Phung SK, Nguyen L, et al. The adrenergic receptor antagonists propranolol and carvedilol decrease bone sarcoma cell viability and sustained carvedilol reduces clonogenic survival and increases radiosensitivity in canine osteosarcoma cells. Vet Comp Oncol. 2020; 18(1): 128140, doi: 10.1111/vco.12560, indexed in Pubmed: 31778284.
  70. Farhood B, Najafi M, Mortezaee K. CD8 cytotoxic T lymphocytes in cancer immunotherapy: A review. J Cell Physiol. 2019; 234(6): 85098521, doi: 10.1002/jcp.27782, indexed in Pubmed: 30520029.
  71. Nissen MD, Sloan EK, Mattarollo SR. b-Adrenergic Signaling Impairs Antitumor CD8 T-cell Responses to B-cell Lymphoma Immunotherapy. Cancer Immunol Res. 2018; 6(1): 98109, doi: 10.1158/2326-6066.CIR-17-0401, indexed in Pubmed: 29146881.
  72. Oh MS, Guzner A, Wainwright DA, et al. The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors. Clin Lung Cancer. 2021; 22(1): e57e62, doi: 10.1016/j.cllc.2020.07.016, indexed in Pubmed: 32900613.
  73. Carrasco R, Castillo RL, Gormaz JG, et al. Role of Oxidative Stress in the Mechanisms of Anthracycline-Induced Cardiotoxicity: Effects of Preventive Strategies. Oxid Med Cell Longev. 2021; 2021: 8863789, doi: 10.1155/2021/8863789, indexed in Pubmed: 33574985.
  74. Songbo M, Lang H, Xinyong C, et al. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett. 2019; 307: 4148, doi: 10.1016/j.toxlet.2019.02.013, indexed in Pubmed: 30817977.
  75. Sawicki KT, Sala V, Prever L, et al. Preventing and Treating Anthracycline Cardiotoxicity: New Insights. Annu Rev Pharmacol Toxicol. 2021; 61: 309332, doi: 10.1146/annurev-pharmtox-030620-104842, indexed in Pubmed: 33022184.
  76. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR, et al. Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: The CECCY Trial. J Am Coll Cardiol. 2018; 71(20): 22812290, doi: 10.1016/j.jacc.2018.02.049, indexed in Pubmed: 29540327.
  77. Barbosa RR, Bourguignon TB, Torres LD, et al. Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers. Rev Assoc Med Bras (1992). 2018; 64(8): 745754, doi: 10.1590/1806-9282.64.08.745, indexed in Pubmed: 30673046.
  78. Huang S, Zhao Q, Yang ZG, et al. Protective role of beta-blockers in chemotherapy-induced cardiotoxicity-a systematic review and meta-analysis of carvedilol. Heart Fail Rev. 2019; 24(3): 325333, doi: 10.1007/s10741-018-9755-3, indexed in Pubmed: 30523513.
  79. Guglin M, Krischer J, Tamura R, et al. Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer. J Am Coll Cardiol. 2019; 73(22): 28592868, doi: 10.1016/j.jacc.2019.03.495, indexed in Pubmed: 31171092.
  80. Cochera F, Dinca D, Bordejevic DA, et al. Nebivolol effect on doxorubicin-induced cardiotoxicity in breast cancer. Cancer Manag Res. 2018; 10: 20712081, doi: 10.2147/CMAR.S166481, indexed in Pubmed: 30038521.
  81. Mohamed EA, Kassem HH. Protective effect of nebivolol on doxorubicin-induced cardiotoxicity in rats. Arch Med Sci. 2018; 14(6): 14501458, doi: 10.5114/aoms.2018.79008, indexed in Pubmed: 30393501.
  82. Cadeddu Dessalvi C, Deidda M, Noto A, et al. Antioxidant Approach as a Cardioprotective Strategy in Chemotherapy-Induced Cardiotoxicity. Antioxid Redox Signal. 2021; 34(7): 572588, doi: 10.1089/ars.2020.8055, indexed in Pubmed: 32151144.
  83. Shoukat S, Zheng D, Yusuf SW. Cardiotoxicity Related to Radiation Therapy. Cardiol Clin. 2019; 37(4): 449458, doi: 10.1016/j.ccl.2019.07.010, indexed in Pubmed: 31587786.
  84. Madan R, Benson R, Sharma DN, et al. Radiation induced heart disease: Pathogenesis, management and review literature. J Egypt Natl Canc Inst. 2015; 27(4): 187193, doi: 10.1016/j.jnci.2015.07.005, indexed in Pubmed: 26296945.
  85. Curigliano G, Lenihan D, Fradley M, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020; 31(2): 171190, doi: 10.1016/j.annonc.2019.10.023, indexed in Pubmed: 31959335.
  86. Ni J, Zhang Li. Cancer Cachexia: Definition, Staging, and Emerging Treatments. Cancer Manag Res. 2020; 12: 55975605, doi: 10.2147/CMAR.S261585, indexed in Pubmed: 32753972.
  87. Argilés JM, López-Soriano FJ, Stemmler B, et al. Therapeutic strategies against cancer cachexia. Eur J Transl Myol. 2019; 29(1): 7960, doi: 10.4081/ejtm.2019.7960, indexed in Pubmed: 31019661.
  88. Belloum Y, Rannou-Bekono F, Favier FB. Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review). Oncol Rep. 2017; 37(5): 25432552, doi: 10.3892/or.2017.5542, indexed in Pubmed: 28393216.
  89. Barkhudaryan A, Scherbakov N, Springer J, et al. Cardiac muscle wasting in individuals with cancer cachexia. ESC Heart Fail. 2017; 4(4): 458467, doi: 10.1002/ehf2.12184, indexed in Pubmed: 29154433.
  90. Rolfe M, Kamel A, Ahmed MM, et al. Pharmacological management of cardiac cachexia: a review of potential therapy options. Heart Fail Rev. 2019; 24(5): 617623, doi: 10.1007/s10741-019-09784-3, indexed in Pubmed: 30923991.
  91. Murphy KT. The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am J Physiol Heart Circ Physiol. 2016; 310(4): H466H477, doi: 10.1152/ajpheart.00720.2015, indexed in Pubmed: 26718971.
  92. Stewart Coats AJ, Ho GF, Prabhash K, et al. for and on behalf of the ACT-ONE study group. Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial). J Cachexia Sarcopenia Muscle. 2016; 7(3): 355365, doi: 10.1002/jcsm.12126, indexed in Pubmed: 27386169.
  93. Zhong S, Yu D, Zhang X, et al. b-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Eur J Cancer Prev. 2016; 25(5): 440448, doi: 10.1097/CEJ.0000000000000192, indexed in Pubmed: 26340056.
  94. Choi CH, Song T, Kim TH, et al. Meta-analysis of the effects of beta blocker on survival time in cancer patients. J Cancer Res Clin Oncol. 2014; 140(7): 11791188, doi: 10.1007/s00432-014-1658-7, indexed in Pubmed: 24671228.
  95. Na Z, Qiao X, Hao X, et al. The effects of beta-blocker use on cancer prognosis: a meta-analysis based on 319,006 patients. Onco Targets Ther. 2018; 11: 49134944, doi: 10.2147/OTT.S167422, indexed in Pubmed: 30174436.
  96. Powe D, Voss M, Zänker K, et al. Beta-Blocker Drug Therapy Reduces Secondary Cancer Formation in Breast Cancer and Improves Cancer Specific Survival. Oncotarget. 2010; 1(7): 628638, doi: 10.18632/oncotarget.197.
  97. Yap A, Lopez-Olivo MA, Dubowitz J, et al. Effect of beta-blockers on cancer recurrence and survival: a meta-analysis of epidemiological and perioperative studies. Br J Anaesth. 2018; 121(1): 4557, doi: 10.1016/j.bja.2018.03.024, indexed in Pubmed: 29935594.
  98. Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Oncogenic. 2019; 173(2): 321337, doi: 10.1016/j.cell.2018.03.035.
  99. Cullen J, Breen M. An Overview of Molecular Cancer Pathogenesis, Prognosis, and Diagnosis. Tumors in Domestic Animals. 2016: 126, doi: 10.1002/9781119181200.ch1.
  100. Rafiemanesh H, Mehtarpour M, Khani F, et al. Epidemiology, incidence and mortality of lung cancer and their relationship with the development index in the world. J Thorac Dis. 2016; 8(6): 10941102, doi: 10.21037/jtd.2016.03.91, indexed in Pubmed: 27293825.
  101. Weberpals J, Jansen L, Carr PR, et al. Beta blockers and cancer prognosis - The role of immortal time bias: A systematic review and meta-analysis. Cancer Treat Rev. 2016; 47: 111, doi: 10.1016/j.ctrv.2016.04.004, indexed in Pubmed: 27179912.
  102. Weberpals J, Jansen L, van Herk-Sukel MPP, et al. Immortal time bias in pharmacoepidemiological studies on cancer patient survival: empirical illustration for beta-blocker use in four cancers with different prognosis. Eur J Epidemiol. 2017; 32(11): 10191031, doi: 10.1007/s10654-017-0304-5, indexed in Pubmed: 28864947.