The roles of beta-adrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms

Lương, Khanh vinh quốc; Nguyễn, Lan

doi:10.2147/cmar.s39153

Cited by 19 publications

(14 citation statements)

References 256 publications

(257 reference statements)

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“…Literature data showed that β-ARs blockade could be involved in prevention and treatment of different types of tumor [21]. Preclinical and clinical efficacy of β-ARs blockade in numerous cancers, including breast cancer, melanoma, angiosarcoma, neuroblastoma, pancreatic adenocarcinoma, ovarian and prostate cancer, has been demonstrated [22].…”

Section: Discussionmentioning

confidence: 99%

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance

Calvani

Dabraio

Bruno

et al. 2020

IJMS

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β-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (β3-AR) is associated with different tumor conditions. Currently, there are few data concerning β3-AR in myeloid malignancies. Here, we evaluated β3-AR in myeloid leukemia cell lines and the effect of β3-AR antagonist SR59230A. In addition, we investigated the potential role of β3-AR blockade in doxorubicin resistance. Using flow cytometry, we assessed cell death in different in vitro myeloid leukemia cell lines (K562, KCL22, HEL, HL60) treated with SR59230A in hypoxia and normoxia; furthermore, we analyzed β3-AR expression. We used healthy bone marrow cells (BMCs), peripheral blood mononuclear cells (PBMCs) and cord blood as control samples. Finally, we evaluated the effect of SR59230A plus doxorubicin on K562 and K562/DOX cell lines; K562/DOX cells are resistant to doxorubicin and show P-glycoprotein (P-gp) overexpression. We found that SR59230A increased cancer cell lines apoptosis especially in hypoxia, resulting in selective activity for cancer cells; moreover, β3-AR expression was higher in malignancies, particularly under hypoxic condition. Finally, we observed that SR59230A plus doxorubicin increased doxorubicin resistance reversion mainly in hypoxia, probably acting on P-gp. Together, these data point to β3-AR as a new target and β3-AR blockade as a potential approach in myeloid leukemias.

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Section: Discussionmentioning

confidence: 99%

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance

Calvani

Dabraio

Bruno

et al. 2020

IJMS

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“…Recently, emerging evidence has demonstrated the association between β-adrenergic antagonism and cancer. β-adrenergic antagonists also exert antitumor effects via non-genomic mechanisms, including matrix metalloproteinase, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, oxidative stress and nitric oxide synthase; thus, treatment with these antagonists may exert a beneficial clinical effect in patients with cancer ( 8 ). The present study demonstrated that ADRB2 was highly expressed in human HCC cells; ADBR2 antagonism attenuated HCC cell growth by inducing cell apoptosis and G 2 /M phase cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

“…The β 2 adrenergic receptor (ADRB2) is a member of the superfamily of adrenergic G-protein-coupled receptors (GPCRs), and is widely expressed in the majority of cell types ( 6 ); it is the primary target of the catecholamine epinephrine during the stress response ( 7 ). Previous studies have demonstrated that the activation of ADRB2 can stimulate several signaling pathways, including the Ras-mediated Raf proto-oncogene serine/threonine-protein kinase (Raf)/dual specificity mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/RAC serine/threonine-protein kinase (Akt) and cAMP/protein kinase A/mitogen-activated protein kinase pathways that promote cellular proliferation and invasion, and suppress apoptosis in cancer cells, which can enhance tumor growth and facilitate metastasis ( 8 ). β-adrenergic blockers have been used clinically to reduce the rates of progression of several types of solid tumor ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of human hepatocellular carcinoma cells by antagonism of the β2 adrenergic receptor

2018

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Previous studies have shown that the activation of the β2 adrenergic receptor (ADRB2) can stimulate several signaling pathways that promote tumor growth and metastasis. β-adrenergic antagonism may have a beneficial role in cancer treatment; however, little is known about the effect of ADRB2 inhibition on the growth of human hepatocellular carcinoma (HCC) cells. The present study revealed that ADRB2 was highly expressed in HCC cell lines compared with that in a normal liver cell line. Treatment with the ADRB2 antagonists ICI118,551 and metoprolol significantly inhibited the growth of human HCC cells. Annexin V/propidium iodide apoptosis and Hoechst staining assays revealed that treatment with ADRB2 antagonists induced apoptosis in HCC cells. Additionally, cell cycle analysis using propidium iodide staining demonstrated that growth suppression was associated with G2/M phase cell cycle arrest by ADRB2 antagonism in HCC cells. Treatment with the ADRB2 antagonists suppressed HCC growth, possibly through inhibiting expression of B-cell lymphoma-2 (Bcl-2) and upregulating that of caspase-9 and Bcl-2-associated X, as well as downregulating the expression levels of the G2/M phase-associated proteins cyclin B1 and cyclin-dependent kinase 1. Therefore, the observations of the present study indicate that ADRB2 blockade inhibited HCC growth, potentially mediated by inducing apoptosis and G2/M phase cell cycle arrest. ADRB2 antagonists may therefore be a promising therapeutic strategy for HCC.

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“…[23][24][25][26][27] Expression of immunoreactivities for alpha-adrenergic receptors (α-AR) and beta-adrenergic receptors (β-AR) has been shown to correlate with aggressive biologic behaviour in cancer cells. [28][29][30][31] The biological effects of norepinephrine and epinephrine are mediated by α-ARs and β-ARs, which have distinct patterns of tissue distribution within the body. 32 The three subtypes of β-ARs (β1-AR, β2-AR, β3-AR) have been shown to present at several sites of primary and metastatic tumour growth and studies suggest they may play a role in biologic processes such as proliferation, metastasis and angiogenesis.…”

Section: Inroductionmentioning

confidence: 99%

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

Duckett

Phung

Linh-Trung

et al. 2019

Vet Comparative Oncology

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Adrenergic receptor (AR) expression has been demonstrated at several sites of primary and metastatic tumour growth and may influence proliferation, survival, metastasis and angiogenesis. AR antagonists like propranolol and carvedilol inhibit proliferation, induce apoptosis and synergize with chemotherapy agents in some cancers. Radiation resistance is mediated in many cells by upregulation of pro‐survival pathways, which may be influenced by ARs. Studies evaluating AR antagonists combined with radiation are limited. The purpose of this study was to determine the effect of propranolol and carvedilol on viability and radiosensitivity in sarcoma cell lines. The hypothesis was that propranolol and carvedilol would increase radiosensitivity in four primary bone sarcoma cell lines. Single agent propranolol or carvedilol inhibited cell viability in all cell lines in a concentration‐dependent manner. The mean inhibitory concentrations (IC50) for carvedilol were approximately 4‐fold lower than propranolol and may be clinically relevant in vivo. Immunoblot analysis confirmed AR expression in both human and canine sarcoma cell lines; however, there was no correlation between baseline AR protein expression and radiosensitivity. Short duration treatment with carvedilol and propranolol did not significantly affect clonogenic survival. Prolonged exposure to propranolol and carvedilol significantly decreased the surviving fraction of canine osteosarcoma cells after 3Gy radiation. Based on our results and possible in vivo activity in dogs, further studies investigating the effects of carvedilol on sarcoma are warranted.

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The roles of beta-adrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms

Cited by 19 publications

References 256 publications

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance

Growth inhibition of human hepatocellular carcinoma cells by antagonism of the β2 adrenergic receptor

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

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