Importance of adrenergic pathways in women's cancers

Thaker, Premal H.; Sood, Anil K.; Ramondetta, Lois M.

doi:10.3233/cbm-130324

Cited by 16 publications

(23 citation statements)

References 84 publications

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“…Authors have extensively detailed and elucidated mechanisms contributing to β adrenergic receptor modulated signaling, dynamics, and regulation [11-16, 47, 154], pharmacological modulation of which may powerfully modify tumor cell proliferation, motility, immunogenicity, elaboration of protein mediators promoting angiogenesis, and invasive and metastatic potential [124,154]. Studies have alternately demonstrated amplification or attenuation of cellular proliferation of gliomas [6,39,40] and extra-neuraxial carcinomas in response to pharmacological enhancement of β adrenergic receptor modulated signaling [8,45,46,49,51,52,54,57,63,152]. The character of βagonist utilized, tumor model and preparation type, receptor regulation dynamics, and differential distal signal transduction mechanisms may explain inter-experimental differences.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have provided evidence indicating ligand activation of β adrenergic receptor modulated signaling may either promote or blunt proliferation of malignantly transformed cells in glioma models [4,[38][39][40][41][42][43][44] and extra-neuraxial carcinoma [45][46][47][48][49]. Specifically, ligand activation of β adrenergic receptors potently amplifies cellular proliferation in lung [7], gastric [50], hepatocellular [51], pancreatic [52], colorectal [53], breast [54,55], ovarian [56,57], and prostatic [49] carcinoma models in vitro. Paradoxically, pharmacological antagonism of β adrenergic receptors also potently attenuates cellular proliferation in hemangioblastoma [58] and hepatic [55], pancreatic [59], gastric [50], colorectal [46], breast [54,55], ovarian, and prostatic [60] carcinoma models in vitro.…”

Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

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RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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Neoplastically transformed astrocytes express functionally active cell surface β adrenergic receptors (βARs). Treatment of glioma models in vitro and in vivo with β adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, β adrenergic agonists generally reduce cellular proliferation. However, treatment with β adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. β adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with β adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate βagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of β adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. β adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the β adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the β adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the β adrenergic receptor induces its phosphorylation by β adrenergic receptor kinase (βARK), rendering it a suitable substrate for alternate binding by β arrestins 1 or 2. The binding of a β arrestin to βARK phosphorylated βAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the βAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, βAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the β adrenergic receptor favoring β arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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“…The ubiquity of catecholamine signalling and the apparent expression of adrenergic receptors in multiple tumour types would suggest that the effects of PRO may extend, ultimately, to a much larger number of cancer types than has hitherto been suggested [203–204]. In the meantime there is a good level of evidence for further investigation in pancreatic cancer and neuroblastoma, particularly in combination with other agents, including repurposed drugs such as ketorolac or etodolac.…”

Section: Our Takementioning

confidence: 99%

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

Pantziarka

Bouche

Sukhatme³

et al. 2016

ecancer

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Propranolol (PRO) is a well-known and widely used non-selective beta-adrenergic receptor antagonist (beta-blocker), with a range of actions which are of interest in an oncological context. PRO displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumour cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. In particular there is evidence that PRO is effective at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response. Based on this evidence the case is made for further clinical investigation of the anticancer effects of PRO, particularly in combination with other agents. A number of trials are on-going, in different treatment settings for various cancers.

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“…Depressed mood is quite prevalent in ovarian cancer patients and has been associated with elevated NE in both healthy individuals (Hughes, Watkins, Blumenthal, Kuhn, & Sherwood, 2004) and in ovarian cancer patients (Lutgendorf et al, 2009). Both oxidative stress (Reuter et al, 2010) and adrenergic signaling have been shown to modulate numerous pathways implicated in tumor progression (Thaker, Sood, & Ramondetta, 2013) and thus their interaction could potentially be involved in tumor progression. Therefore, the purpose of this study was to determine levels of antioxidant enzyme activity in primary ovarian tumor tissue and to investigate associations of mood and tumor NE with the antioxidant enzymes MnSOD and GPx.…”

Section: Introductionmentioning

confidence: 99%

Biobehavioral and neuroendocrine correlates of antioxidant enzyme activity in ovarian carcinoma

Bayer

Spitz

Christensen

et al. 2015

Brain, Behavior, and Immunity

Self Cite

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Increased levels of reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide have been reported in many cancer cells and they have been implicated in carcinogenesis and tumor progression. Antioxidant enzymes, such as Manganese Superoxide Dismutase (MnSOD or SOD2) and Glutathione Peroxidase-1 (GPx1), act coordinately to neutralize ROS. These enzymes are also thought to contribute to cancer cell resistance to conventional radio-chemotherapies. Although some relationships have been reported between psychosocial factors and the regulation of antioxidant enzymes, little is known about these relationships in the context of cancer progression. The current study investigated the levels of MnSOD and GPx1 in confirmed serous, high-grade tumor tissue from 60 ovarian cancer patients, and explored the relationship between the activity of these enzymes, the levels of tumor norepinephrine (NE), and patient mood as determined via pre-operative questionnaires. MnSOD activity was positively related to depressed mood (p = 0.025) and tumor NE (p = 0.023). In contrast, GPx1 activity was inversely related to fatigue (p = 0.015) and tumor NE (p = 0.009), and was positively associated with vigor (p = 0.024). These findings suggest that psychological state and adrenergic signaling are linked with antioxidant enzyme activity in ovarian cancer and may have implications for patient treatments and outcomes.

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Importance of adrenergic pathways in women's cancers

Cited by 16 publications

References 84 publications

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

Biobehavioral and neuroendocrine correlates of antioxidant enzyme activity in ovarian carcinoma

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