Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF

González, Alicia; González-González, Alicia; Alonso‐González, Carolina; Menéndez-Menéndez, Javier; Martínez‐Campa, Carlos; Cos, Samuel

doi:10.3892/or.2017.5446

Cited by 39 publications

(30 citation statements)

References 37 publications

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“…The same antiangiogenic properties of melatonin, mediated through a decline in the levels of VEGF has been described in several kind of tumors, such as neuroblastoma 52 , breast cancer 22,23 , ovarian 53 , gastric 54 , pancreatic 55 , prostate 56 or hepatocarcinoma 57 . Additionally, the pineal hormone concomitantly administered with cyclophosphamide reduced VEGF-A transcription and tumor growth, both in salivary glands and Walker 256 carcinoma 58 .…”

Section: Discussionsupporting

confidence: 52%

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process

González-González

González

Rueda

et al. 2020

Sci Rep

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chemotherapeutics are sometimes administered with drugs, like antiangiogenic compounds, to increase their effectiveness. Melatonin exerts antitumoral actions through antiangiogenic actions. We studied if melatonin regulates the response of HUVECs to chemotherapeutics (docetaxel and vinorelbine). The inhibition that these agents exert on some of the processes involved in angiogenesis, such as, cell proliferation, migratory capacity or vessel formation, was enhanced by melatonin. Regarding to estrogen biosynthesis, melatonin impeded the negative effect of vinorelbine, by decreasing the activity and expression of aromatase and sulfatase. Docetaxel and vinorelbine increased the expression of VEGF-A, VEGF-B, VEGF-C, VEGFR-1, VEGFR-3, ANG1 and/or ANG-2 and melatonin inhibited these actions. Besides, melatonin prevented the positive actions that docetaxel exerts on the expression of other factors related to angiogenesis like JAG1, ANPEP, IGF-1, CXCL6, AKT1, ERK1, ERK2, MMP14 and NOS3 and neutralized the stimulating actions of vinorelbine on the expression of FIGF, FGFR3, CXCL6, CCL2, ERK1, ERK2, AKT1, NOS3 and MMP14. In CAM assay melatonin inhibited new vascularization in combination with chemotherapeutics. Melatonin further enhanced the chemotherapeutics-induced inhibition of p-AKt and p-eRK and neutralized the chemotherapeuticscaused stimulatory effect on HUVECs permeability by modifying the distribution of VE cadherin. Our results confirm that melatonin blocks proangiogenic and potentiates antiangiogenic effects induced by docetaxel and vinorelbine enhancing their antitumor effectiveness.The development of new blood vessels is needed to provide oxygen and nutrients to the tumor cells and a way to escape from the primary site 1 . Angiogenesis is a main step in tumor growth and antiangiogenic agents are considered an interesting complementary strategy in cancer therapy 2 . Angiogenesis is a multi-step process: endothelial cell activation by growth factors, degradation of capillary wall by proteinases, formation of a branch point in the vessel wall, migration of endothelial cells and proliferation and reorganisation of endothelial cells to form tubules. In tumors, the interaction between endothelial cells and the microenvironment stimulates endothelial cells to proliferate, migrate and form a branching network of tubes 3 . A balance between angiogenic activating and inhibiting factors regulates the evolution of endothelial cells from a quiescent to a proangiogenic stage 2 . Among the principal proangiogenic factors are vascular endothelial growth factor (VEGF) and angiopoietins (ANG) 4,5 . Angiogenesis depends on the coordinated balance in time between the production of VEGF and angiopoietins 6 .Melatonin, produced in the pineal gland, has antitumor effects in different cancer types, especially hormone-dependent tumors 7-10 . Melatonin oncostatic actions are exerted through different mechanisms, such as: indirect effects through a down-regulation of gonadal estrogens 11 ; direct antiestrogenic actions at the tumor cell ...

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Section: Discussionsupporting

confidence: 52%

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process

González-González

González

Rueda

et al. 2020

Sci Rep

Self Cite

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“…Furthermore, shift workers have an increased risk for prostate cancer (Dumont et al, 2012), and exposure to artificial light at night is associated with prostate cancer because it disturbs endogenous circadian rhythms leading to the suppression of nocturnal melatonin production (Kim et al, 2016). Melatonin likely affects tumor biology via multiple mechanisms that include the modulation of the redox balance, immune system, angiogenesis, endocrine system, androgen receptors signaling, as well as the direct action via specific membrane receptors (Tam and Shiu, 2011;Gonzalez et al, 2017). In vitro and in vivo models document that melatonin displays a relevant antiproliferative activity in cancer (Bizzarri et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Transdermal administration of melatonin coupled to cryopass laser treatment as noninvasive therapy for prostate cancer

et al. 2017

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Melatonin, a pineal gland hormone, exerts oncostatic activity in several types of human cancer, including prostate, the most common neoplasia and the third most frequent cause of male cancer death in the developed world. The growth of androgen-sensitive LNCaP prostate cancer cells in mice is inhibited by 3 mg/kg/week melatonin (0.09 mg/mouse/week) delivered by i.p. injections, which is equivalent to a dose of 210 mg/week in humans. The aim of this study is to test an alternative noninvasive delivery route based on transdermal administration of melatonin onto the tumor area followed by cryopass-laser treatment. Two groups of immunodepressed mice were studied, one (n ¼ 10) subjected to 18 cryopass-laser therapy sessions and one (n ¼ 10) subjected to the same treatment without melatonin. These groups were compared with mice treated with i.p.-administered melatonin or vehicle with the same time schedule. We found that cryopass-laser treatment is as efficient as i.p. injections in reducing the growth of LNCaP tumor cells, affecting plasma melatonin and redox balance. Furthermore, both delivery routes share the same effects on the involved biochemical pathway driven by hypoxia-inducible factor 1a. However, cryopass-laser, as used in the present experimental setup, is less efficient than i.p delivery route in increasing the melatonin content and Nrf2 expression in the tumor mass. We conclude that cryopass-laser treatment may have impact for melatonin-based therapy of prostate cancer, by delivering drugs transdermally without causing pain and targeting directly on the site of interest, thereby potentially making long-term treatments more sustainable.ARTICLE HISTORY

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“…The mechanisms underlying this are manifold but ultimately lead to a reduction of expression levels of genes required for angiogenesis [104]. Inhibition of expression of vascular endothelial growth factor is a central part of this targeting [105]. Melatonin-promoted inhibition of inflammatory events also plays a role in retarding blood vessel proliferation [106] and melatonin can simultaneously reduce content of angiogenic and inflammatory proteins in a mammary tumor cell line [62].…”

Section: Mechanismsmentioning

confidence: 99%

Mechanisms Underlying Tumor Suppressive Properties of Melatonin

Bondy

Campbell

2018

IJMS

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There is considerable evidence that melatonin may be of use in the prevention and treatment of cancer. This manuscript will review some of the human, animal and cellular studies that provide evidence that melatonin has oncostatic properties. Confirmation that melatonin mitigates pathogenesis of cancer will be described from both direct study of its effects on carcinogenesis, and from indirect findings implicating disruption of the circadian cycle. A distinction is made between the role of melatonin in preventing the initiation of the tumorigenic pathway and the ability of melatonin to retard the progression of cancer. Melatonin appears to slow down the rate of advancement of established tumors and there is evidence that it constitutes a valuable complement to standard pharmacological and radiation treatment modalities. There are instances of the beneficial outcomes in cancer treatment which utilize a range of hormones and vitamins, melatonin being among the constituents of the mix. While these complex blends are empirically promising, they are only briefly mentioned here in view of the confounding influence of a multiplicity of agents studied simultaneously. The last section of this review examines the molecular mechanisms that potentially underlie the oncostatic effects of melatonin. Alterations in gene expression following activation of various transcription factors, are likely to be an important mediating event. These changes in gene activity not only relate to cancer but also to the aging process which underlies the onset of most tumors. In addition, epigenetic events such as modulation of histone acetylation and DNA methylation patterns throughout the lifespan of organisms need to be considered. The antioxidant and immunoregulatory roles of melatonin may also contribute to its cancer modulatory properties. Naturally, these mechanisms overlap and interact extensively. Nevertheless, in the interest of clarity and ease of reading, each is discussed as a separate topic section. The report ends with some general conclusions concerning the clinical value of melatonin which has been rather overlooked and understudied.

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Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF

Cited by 39 publications

References 37 publications

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process

Transdermal administration of melatonin coupled to cryopass laser treatment as noninvasive therapy for prostate cancer

Mechanisms Underlying Tumor Suppressive Properties of Melatonin

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