Beta‐blockers exert potent anti‐tumor effects in cutaneous and uveal melanoma

DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.

Section: Therapeutic Suppression Of Mir-21mentioning

confidence: 99%

Section: Therapeutic Suppression Of Mir-21mentioning

confidence: 99%

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

Melnik

John

Carrera-Bastos

et al. 2020

“…Moreover, there is recent evidence of potent antitumor effects in UM cells following nonselective beta-blocker administration, and concurrent expression of β1 and β2 adrenoceptors in UM specimens. These findings suggest that further investigation is needed in the context of clinical trials for adjuvant scope [ 112 ]. Current clinical trials in the adjuvant setting are summarized in Table 2 .…”

Section: Adjuvant Therapies and Surveillance Of Ummentioning

confidence: 99%

Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

Mallone

Sacchetti

Moramarco

2020

Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.

“…These studies also confirmed the role of β-ARs in the modulation of angiogenesis and demonstrated that non-selective β-AR antagonists, but not β1-AR selective antagonists, promote apoptosis of cancer cells [ 40 , 41 , 42 ]. Propranolol exerts potent anti-tumoral effects, attenuating migration, reducing vascular endothelial growth factor (VEGF) secretion and inducing apoptosis in both cutaneous and uveal melanoma in a dose-dependent manner [ 43 ]. Anti-angiogenic effect of propranolol has also been well described in infantile hemangiomas (IHs) and retinopathy of prematurity [ 39 ].…”

Section: β-Ars In Melanomamentioning

confidence: 99%

Current Therapies and New Targets to Fight Melanoma: A Promising Role for the β3-Adrenoreceptor

Filippi

Bruno

Domazetovic

et al. 2020

Melanoma is one of the most aggressive types of cancer and the most deadly skin cancer. According to World Health Organization, about 132,000 melanoma skin cancers occur globally each year. Thanks to the efficacy of new therapies, life expectation has been improved over the last years. However, some malignant melanomas still remain unresponsive to these therapies. The β-adrenergic system, among its many physiological roles, has been recognized as the main mediator of stress-related tumorigenic events. In particular, catecholamine activation of β-adrenergic receptors (β-ARs) affects several processes that sustain cancer progression. Among the β-AR subtypes, the β3-AR is emerging as an important regulator of tumorigenesis. In this review, we summarize data of different experimental studies focused on β3-AR involvement in tumor development in various types of cancer and, particularly, in melanoma. Taken together, the preclinical evidences reported in this review demonstrate the crucial role of β3-AR in regulating the complex signaling network driving melanoma progression. Therefore, a need exists to further disseminate this new concept and to investigate more deeply the role of β3-AR as a possible therapeutic target for counteracting melanoma progression at clinical level.