Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

Palmieri, Giuseppe; Ombra, Maria Neve; Colombino, Maria; Casula, Milena; Sini, Maria Cristina; Manca, Antonella; Paliogiannis, Panagiotis; Ascierto, Paolo A.; Cossu, Antonio

doi:10.3389/fonc.2015.00183

Cited by 90 publications

(123 citation statements)

References 177 publications

(268 reference statements)

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“…Current evidence suggests the combination of drugs capable of regulating multiple pathways may improve disease control . Therefore, it is crucial to develop new sustainable and effective adjuvant therapeutic options.…”

Section: Discussionmentioning

confidence: 99%

“…40 Current evidence suggests the combination of drugs capable of regulating multiple pathways may improve disease control. 7 Therefore, it is crucial to develop new sustainable and effective adjuvant therapeutic options. Drug repurposing studies are a cost-effective means to find new applications to approved drugs with good safety profiles.…”

Section: Discussionmentioning

confidence: 99%

“…These stress‐related hormones are increased in patients with cancer and their contribution to tumor growth and disease progression has been established including in melanoma . Once activated by catecholamines, β‐AR stimulate several intracellular signal transduction pathways, such as the nitric oxide synthase, related to melanoma development and progression . Primary downstream effects include vasodilation and release of pro‐angiogenic factors, such as vascular endothelial growth factor (VEGF) …”

Section: Introductionmentioning

confidence: 99%

“…6 Once activated by catecholamines, β-AR stimulate several intracellular signal transduction pathways, such as the nitric oxide synthase, related to melanoma development and progression. 7 Primary downstream effects include vasodilation and release of proangiogenic factors, such as vascular endothelial growth factor (VEGF). 5 The therapeutic potential of a non-selective β-blocker in cutaneous melanoma (CM) progression has been partially evaluated.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Background Melanoma is a life‐threatening group of cancers mainly affecting the skin (cutaneous melanoma, CM) and the eyes (uveal melanoma, UM). Nearly half of patients with UM develop liver metastases regardless of the primary treatment. For this reason, adjuvant therapy to prevent disease progression is essential to improve survival of patients with melanoma. Beta‐adrenoceptors (β‐AR) have emerged as novel targets to inhibit tumor growth and dissemination in CM, but have not been investigated in UM. Methods The aim of this study was to comprehensively evaluate the effects of a non‐selective β‐blocker in UM and CM. Propranolol was tested on four UM and two CM cell lines to determine the effects of this beta‐blocker. The expression of β‐AR in UM was assessed in enucleated eyes of 36 patients. Results The results showed that propranolol exerts potent anti‐proliferative effects, attenuates migration, reduces VEGF and induces cell cycle arrest and apoptosis in both UM and CM in a dose‐dependent manner. Furthermore, levels of cell‐free DNA released from the cells correlated to propranolol treatment and may be an indicator of treatment response. Finally, immunohistochemical analysis revealed the expression of β1 and β2 adrenoceptors in all UM patients, with higher expression seen in the more aggressive epithelioid versus less aggressive spindle cells. Conclusions Collectively our data suggest that a nonselective beta‐blocker may be effective against melanoma. For the first time, we show potent anti‐tumor effects in UM cells following propranolol administration and expression of β1 and β2 adrenoceptors in patient tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…This path is considered the main route changed in melanoma and is involved in cell survival, proliferation, and migration, and is related to both development and melanoma progression [2]. So far, the best characterized effectors of RAS proteins are RAF kinase and phosphatidylinositol-3-kinase (PI3K) [3].…”

Section: Introductionmentioning

confidence: 99%

Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma

Toricelli

Melo

Hunger

et al. 2017

Cancers

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High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and β1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics. Timp1 downregulation resulted in decreased anoikis resistance, clonogenicity, dacarbazine resistance, and in vivo tumor growth and lung colonization. In metastatic cells, pAKTThr308 is highly expressed, contributing to anoikis resistance. We showed that PDK1Ser241 and PKCβIISer660 are activated by Timp1 in different stages of melanoma progression, contributing to colony formation and anoikis resistance. Moreover, simultaneous inhibition of Timp1 and AKT in metastatic cells resulted in more effective anoikis inhibition. Our findings demonstrate that Timp1 promotes cell survival with the participation of PDK1 and PKC in melanoma. In addition, Timp1 and AKT act synergistically to confer anoikis resistance in advanced tumor stages. This study brings new insights about the mechanisms by which Timp1 promotes cell survival in melanoma, and points to novel perspectives for therapeutic approaches.

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Nanomedicines as Multifunctional Modulators of Melanoma Immune Microenvironment

Carreira

Acúrcio

Matos

et al. 2020

Advanced Therapeutics

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Melanoma is the most destructive and deadly among skin cancers. Patients presenting the most disseminated form of this disease have very low survival rates (≈15%) and highly restricted therapeutic alternatives. In recent years, the area of cancer immunotherapy has witnessed remarkable developments in the management of many cancers, including melanoma. In fact, immunotherapy unveiled as a feasible therapeutic alternative for late‐stage melanoma patients, specifically using immune checkpoint therapies. However, despite the exciting outcomes, only a small percentage of patients respond to these therapies, and severe immune‐related adverse reactions have been often reported. As such, most of preclinical and clinical studies currently explore melanoma tumor biology and immunology to guide the development of combinational immunotherapies aiming at relevant clinical efficacy and minimal toxicity. Herein, the current knowledge on melanoma biology and immunology is discussed, focusing on nanotechnology as a crucial strategy for the development of combinatorial approaches able to specifically modulate the function of key players responsible for melanoma evolution and evasion of host immune‐mediated attacks. Finally, the major challenges toward the clinical implementation of these emergent targeted nanomedicines for immunotherapy are further discussed, with particular focus on melanoma genomics, predictive biomarkers, clinical trial design, and clinical regulation of nanomedicines.

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Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

Cited by 90 publications

References 177 publications

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

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

Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma

Nanomedicines as Multifunctional Modulators of Melanoma Immune Microenvironment

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