Targeting Melanoma-Initiating Cells by Caffeine: In Silico and In Vitro Approaches

Tabolacci, Claudio; Cordella, Martina; Rossi, Stefania; Bonaccio, Marialaura; Eramo, Adriana; Mischiati, Carlo; Beninati, Simone; Iacoviello, Licia; Facchiano, Antonio; Facchiano, Francesco

doi:10.3390/molecules26123619

Cited by 6 publications

(3 citation statements)

References 68 publications

(84 reference statements)

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“…Collectively, caffeine treatment affects the expression of pro- and anti-angiogenic and inflammatory factors of the retina and choroid endothelium, which could contribute to the effect of caffeine in mitigating ocular inflammation and angiogenesis. A recent study identified tyrosinase as a major target of caffeine action in modulating the proliferation and expression of various immunomodulatory cytokines and chemokines in melanomas ( Tabolacci et al, 2021 ). The role of choroidal melanocytes in immunomodulation and pathogenesis of nAMD, and their response to caffeine remain a subject of future investigation.…”

Section: Discussionmentioning

confidence: 99%

Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

Sorenson

Song

Zaitoun

et al. 2021

Front. Cell Dev. Biol.

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Adenosine receptors (AR) are widely expressed in a variety of tissues including the retina and brain. They are involved in adenosine-mediated immune responses underlying the onset and progression of neurodegenerative diseases. The expression of AR has been previously demonstrated in some retinal cells including endothelial cells and retinal pigment epithelial cells, but their expression in the choroid and choroidal cells remains unknown. Caffeine is a widely consumed AR antagonist that can influence inflammation and vascular cell function. It has established roles in the treatment of neonatal sleep apnea, acute migraine, and post lumbar puncture headache as well as the neurodegenerative diseases such as Parkinson and Alzheimer. More recently, AR antagonism with caffeine has been shown to protect preterm infants from ischemic retinopathy and retinal neovascularization. However, whether caffeine impacts the development and progression of ocular age-related diseases including neovascular age-related macular degermation remains unknown. Here, we examined the expression of AR in retinal and choroidal tissues and cells. We showed that antagonism of AR with caffeine or istradefylline decreased sprouting of thoracic aorta and choroid/retinal pigment epithelium explants in ex vivo cultures, consistent with caffeine’s ability to inhibit endothelial cell migration in culture. In vivo studies also demonstrated the efficacy of caffeine in inhibition of choroidal neovascularization and mononuclear phagocyte recruitment to the laser lesion sites. Istradefylline, a specific AR 2A antagonist, also decreased choroidal neovascularization. Collectively, our studies demonstrate an important role for expression of AR in the choroid whose antagonism mitigate choroidal inflammatory and angiogenesis activities.

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Section: Discussionmentioning

confidence: 99%

Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

Sorenson

Song

Zaitoun

et al. 2021

Front. Cell Dev. Biol.

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“…One of such strategies comprises GLUT inhibitors, being extensively explored for their antineoplastic potential ( 9 ). Natural products like genistein ( 10 ), quercetin ( 11 ), caffeine ( 12 ), phloretin ( 13 ), resveratrol ( 14 ), curcumin ( 15 ), and small synthetic inhibitors like cytochalasin B ( 16 ), fasentin ( 17 ), WZB117 ( 18 ), thiazolidinedione ( 19 ), STF31 ( 20 ), BAY876 ( 21 ), DRB18 ( 22 ), silybin ( 23 , 24 ), and naringenin ( 25 , 26 ) have been explored for their GLUT-inhibiting potential. They are also in various stages of preclinical and clinical trials ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity

Temre

Yadav²,

Goel³

et al. 2022

Front. Oncol.

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Neoplastic cells overexpress glucose transporters (GLUT), particularly GLUT1 and GLUT3, to support altered metabolism. Hence, novel strategies are being explored to effectively inhibit GLUTs for a daunting interference of glucose uptake. Glutor, a piperazine-2-one derivative, is a newly reported pan-GLUT inhibitor with a promising antineoplastic potential. However, several aspects of the underlying mechanisms remain obscure. To understand this better, tumor cells of thymic origin designated as Dalton’s lymphoma (DL) were treated with glutor and analyzed for survival and metabolism regulatory molecular events. Treatment of tumor cells with glutor caused a decrease in cell survival with augmented induction of apoptosis. It also caused a decrease in glucose uptake associated with altered expression of GLUT1 and GLUT3. HIF-1α, HK-2, LDH-A, and MCT1 also decreased with diminished lactate production and deregulated pH homeostasis. Moreover, glutor treatment modulated the expression of cell survival regulatory molecules p53, Hsp70, IL-2 receptor CD25, and C-myc along with mitochondrial membrane depolarization, increased intracellular ROS expression, and altered Bcl-2/BAX ratio. Glutor also enhanced the chemosensitivity of tumor cells to cisplatin, accompanied by decreased MDR1 expression. Adding fructose to the culture medium containing glutor reversed the latter’s inhibitory action on tumor cell survival. These results demonstrate that in addition to inhibited glucose uptake, modulated tumor growth regulatory molecular pathways are also implicated in the manifestation of the antineoplastic action of glutor. Thus, the novel findings of this study will have a long-lasting clinical significance in evaluating and optimizing the use of glutor in anticancer therapeutic strategies.

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“…The research found that caffeine had potent antiproliferative effects on melanoma cells, possibly by promoting melanin production and reducing the secretion of inflammatory signals. Tyrosinase was identified as a key player in mediating caffeine's effects on melanoma, suggesting its importance in these mechanisms [29].…”

Section: Caffeinementioning

confidence: 99%

Nutrient-Based Approaches for Melanoma: Prevention and Therapeutic Insights

Dong,

Wei,

Yang

et al. 2023

Nutrients

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Melanoma, a prevalent and lethal form of skin cancer, remains a formidable challenge in terms of prevention and treatment. While significant progress has been made in understanding its pathogenesis and treatment, the quest for effective prevention strategies and therapeutic approaches remains ongoing. Considering the increased advancements in understanding the dynamic interplay between nutrients and melanoma, we aim to offer a refreshed perspective on nutrient-based approaches for melanoma prevention and adjunctive therapy. In contrast to other studies, we have innovatively provided a detailed exposition of the nutrients’ influences on melanoma prognosis and treatment. This review firstly examines various nutrients, including antioxidants (namely vitamins A, D, C, and E; selenium; and caffeine), polyunsaturated fatty acids, and flavonoids, for their effects and underlying mechanisms in reducing melanoma risk. Among these nutrients, caffeine shows the most promising potential, as it is supported by multiple cohort studies for its protective effect against melanoma. In contrast, there is a certain degree of inconsistency in the research of other nutrients, possibly due to inherent differences between animal studies and epidemiological research, as well as variations in the definition of nutrient intake. To comprehensively investigate the impact of nutrients on melanoma progression and therapeutic approaches, the following sections will explore how nutrients influence immune responses and other physiological processes. While there is robust support from cell and animal studies regarding the immunomodulatory attributes of vitamins D and zinc, the anti-angiogenic potential of polyphenols, and the cell growth-inhibitory effects of flavonoids, the limited availability of human-based research substantially constrains their practical relevance in clinical contexts. As for utilizing nutrients in adjuvant melanoma treatments, multiple approaches have garnered clinical research support, including the utilization of vitamin D to decrease the postoperative recurrence rates among melanoma patients and the adoption of a high-fiber diet to enhance the effectiveness of immunotherapy. In general, the effects of most nutrients on reducing the risk of melanoma are not entirely clear. However, several nutrients, including vitamin D and dietary fiber, have demonstrated their potential to improve the melanoma prognosis and enhance the treatment outcomes, making them particularly deserving of clinical attention. A personalized and interdisciplinary approach, involving dermatologists, oncologists, nutritionists, and researchers, holds the promise of optimizing melanoma treatment strategies.

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Targeting Melanoma-Initiating Cells by Caffeine: In Silico and In Vitro Approaches

Cited by 6 publications

References 68 publications

Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity

Nutrient-Based Approaches for Melanoma: Prevention and Therapeutic Insights

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