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

Abstract

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 ...

Melatonin as an Oncostatic Molecule Based on Its Anti-Aromatase Role in Breast Cancer

“…One chemotherapeutic agent, vinorelbine, disrupts capillary tubule area formation by approximately 75% in human umbilical vein endothelial cells (HUVECs) as compared with non-treated controls, and this effect of vinorelbine is intensified by 1 mM melatonin treatment, suggesting that this pineal molecule could be a potential anti-angiogenic agent [ 23 ]. Apart from its benefits, vinorelbine may increase aromatase activity.…”

“…Apart from its benefits, vinorelbine may increase aromatase activity. Intriguingly, melatonin has been found to counteract the stimulatory effect of vinorelbine on aromatase activity by downregulating aromatase promoter I.7, which is one of the major aromatase promoters provoking aromatase transcription in breast cancer [ 23 ]. In other words, melatonin supplements the shortcomings, as well as highlights the advantages of chemotherapeutic agents.…”

“…Melatonin is able to selectively neutralize the estrogenic effects on the breast [ 22 ]. The oncostatic roles of melatonin are based on its diverse effects, including its antioxidative properties, apoptosis induction, and anticancer immunity [ 23 ]. Interestingly, melatonin is able to protect normal cells from the cytotoxicity accompanied by ionizing radiation (IR).…”

Structural and physico-chemical evaluation of melatonin and its solution-state excited properties, with emphasis on its binding with novel coronavirus proteins

“…Melatonin is involved in the aging process, growth towards puberty, and modulation of blood pressure [ 21 ]. This versatile compound blocks proangiogenic and antiangiogenic effects caused by docetaxel and vinorelbine, which are anti-tumor drugs, and it enhances their tumor-fighting behavior [ 22 ]. This molecule can modify the redox state of the rat pancreatic stellate cell.…”

Melatonin: A Powerful Integrative Adjunctive Agent for Oncology

“…were all intensified by melatonin [50]. Specific to estrogen biosynthesis, melatonin also reduced the negative impact of vinorelbine by inhibiting the expression and activity of aromatase and sulfatase [50]. This indicates that estrogens are crucial in the tumorigenesis and progression process for at least some forms of cancer.…”