Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment

Galvan, Dana; Ayyappan, Anoop P.; Bryan, Brad Allen

doi:10.18632/oncoscience.472

Cited by 12 publications

(14 citation statements)

References 36 publications

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“…Taking into account Propranolol's β1-2 antagonist activity and success in off-label clinical trials for rare cancer (melanoma, angiosarcoma, and metastasic paraganglioma), we think that ICI may show similar therapeutical properties for the same type of rare carcinomas, avoiding the β1 blocking vascular effect. In addition, tumours like clear cell renal carcinomas (ccRCC) where VHL is mutated arise as a potential target for β-blockers [55][56][57][58] .…”

Section: Discussionmentioning

confidence: 99%

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Cuesta

Albiñana

Gallardo-Vara

et al. 2019

Sci Rep

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One of the major consequences of the lack of a functional VHL protein in von Hippel-Lindau disease, a rare cancer, is the constitutive activation of the HIF pathway. This activation ends up in the generation of Central Nervous System (CNS) Hemangioblastomas among other tumours along the lifespan of the patient. Nowadays, only surgery has been proven efficient as therapy since the systemic attempts have failed. Propranolol, a non-specific β1-and β2-adrenergic receptor antagonist, was recently designated as the first therapeutic (orphan) drug for VHL disease. Nevertheless, its β1 affinity provokes the decrease in blood pressure, being not recommended for low or regular blood pressure VHL patients. In order to overcome the β1-drawback, the properties of a high specific β2-adrenergic receptor blocker named ICI-118,551 have been studied. ICI-118,551 was able to decrease Hemangioblastomas cell viability in a specific manner, by triggering apoptosis. Moreover, ICI-118,551 also impaired the nuclear internalization of HIF-1α in Hemangioblastomas and hypoxic primary endothelial cells, reducing significantly the activation of HIF-target genes and halting the tumour-related angiogenic processes. In this work, we demonstrate the therapeutical properties of ICI-118,551 in VHL-derived CNS-Hemangioblastoma primary cultures, becoming a promising drug for VHL disease and other HIF-related diseases. Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited genetic disorder with an incidence of 1 per 36,000 individuals in the general population and is considered as a rare disease or rare cancer 1,2. Patients with VHL disease harbour a single mutation allele in the tumour suppressor gene VHL (3p25-p26). VHL protein (pVHL) controls the cytoplasmic levels of the Hypoxia Inducible Factor (HIF) complex. In normoxic conditions, pVHL binds to the previously hydroxylated prolyl residues of HIF-1α and HIF-2α, being ubiquitinated and targeted to the proteasome for rapid degradation. When patients suffer a spontaneous inactivation or loss of the second wild-type VHL allele (loss of heterozygosity), either there is no expression of the pVHL or the mutated form is not functional 3,4. Therefore, in the absence of functional pVHL, HIF-1α and HIF-2α subunits accumulate within the cytoplasm and translocate to the nucleus, triggering the hypoxia program by targeting hypoxia responsive genes, which are normally silenced in normoxia 5. HIF-1α and HIF-2α are involved in cell proliferation, angiogenesis, extracellular matrix degradation, vascular tone, and erythropoiesis, among other processes. Hence, cells from VHL tumours have a constitutively active HIF program (a pseudo-hypoxic state) due to the absence of functional pVHL 6,7. As a consequence of this pseudo-hypoxic state, the clinical manifestations of the disease include multiple benign and malignant tumours that appear throughout the lifespan of the patient: retinal hemangioblastoma,

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Section: Discussionmentioning

confidence: 99%

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Cuesta

Albiñana

Gallardo-Vara

et al. 2019

Sci Rep

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“…There is increasing interest in using the non-selective betaadrenoceptor (beta1 and beta2) blocking drug, propranolol, to prevent or treat various malignancies in human subjects [31,41]. Cancer cells, in a given case, however, need not manufacture their own NE/EPI nor release it in an autocrine fashion to be susceptible to propranolol treatment, since this drug or related ones (carvedilol, nebivolol) may help lower blood sugar via modulation of insulin release by the pancreas or increasing insulin sensitivity [136,137].…”

Section: Propranololmentioning

confidence: 99%

“…A number of preclinical and clinical studies now also suggest favorable effects of propranolol on angiosarcoma, a difficult to treat malignancy with a poor prognosis [37][38][39][40][41]. There are also a number of ongoing clinical trials for propranolol in a variety of other neoplasms.…”

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confidence: 99%

Norepinephrine release may play a critical role in the Warburg effect: an integrative model of tumorigenesis

Fitzgerald¹

2020

neo

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Many cancer cells share the property of carrying out markedly elevated rates of glycolysis to generate energy even in the presence of sufficient oxygen, and this is known as the Warburg effect. In recent years, there has been a resurgence of interest in the Warburg effect, as the field of oncology has amassed evidence that cellular metabolism may play a prominent role in many neoplasms. Largely in the past decade, another prominent and perhaps surprising factor has emerged in the cancer literature: the catecholamine molecules, epinephrine (adrenaline) and norepinephrine (noradrenaline), appear to play a role in tumorigenesis and metastasis. The drug propranolol, which blocks beta-adrenergic receptors, may be therapeutic in human angiosarcoma, melanoma, and ovarian cancer. The current paper synthesizes these older and more recent findings, in an attempt to unify the major factors that contribute to tumorigenesis. This paper suggests that in addition to the direct interaction of catecholamine signaling with genetic risk factors (including mutagenesis), it interacts with environmental factors such as hypertension, obesity, unhealthy dietary components, physical inactivity, substance abuse, and mental or emotional stress, to promote the Warburg effect by facilitating glucose availability through suppression of pancreatic insulin release. Further, it proposes that many cancer cells synthesize and release catecholamines to activate their own receptors in an autocrine fashion. In summary, catecholamines are an important "new" factor in cancer that may interface with both genetics and environmental factors to alter the Warburg effect and modulate tumorigenesis.

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“…The beta adrenergic receptor (β‐AR) antagonist, propranolol is a promising agent for the treatment of human angiosarcoma, where its use has increased overall patient survival when combined with chemotherapy . Among these studies, Pasquier et al combined oral propranolol with metronomic chemotherapy in seven patients with advanced angiosarcomas for up to 12 months, followed by propranolol‐containing maintenance therapy.…”

Section: Targeting Cancer Metabolismmentioning

confidence: 99%

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Borgatti

Dickerson

Lawrence

2019

Vet Comparative Oncology

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Sarcomas represent a group of genomically chaotic, highly heterogenous tumours of mesenchymal origin with variable mutational load. Conventional therapy with surgery and radiation therapy is effective for managing small, low‐grade sarcomas and remains the standard therapeutic approach. For advanced, high‐grade, recurrent, or metastatic sarcomas, systemic chemotherapy provides minimal benefit, therefore, there is a drive to develop novel approaches. The discovery of “Coley's toxins” in the 19th century, and their use to stimulate the immune system supported the application of unconventional therapies for the treatment of sarcomas. While promising, this initial work was abandoned and treatment paradigm and disease course of sarcomas was largely unchanged for several decades. Exciting new therapies are currently changing treatment algorithms for advanced carcinomas and melanomas, and similar approaches are being applied to advance the field of sarcoma research. Recent discoveries in subtype‐specific cancer biology and the identification of distinct molecular targets have led to the development of promising targeted strategies with remarkable potential to change the landscape of sarcoma therapy in dogs. The purpose of this review article is to describe the current standard of care and limitations as well as emerging approaches for sarcoma therapy that span many of the most active paradigms in oncologic research, including immunotherapies, checkpoint inhibitors, and drugs capable of cellular metabolic reprogramming.

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Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment

Cited by 12 publications

References 36 publications

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Norepinephrine release may play a critical role in the Warburg effect: an integrative model of tumorigenesis

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

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