Melatonin as an adjuvant to antiangiogenic cancer treatments

Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.Funding: The present study was funded by grants from the Spanish Economy and Competitiveness Ministry (SAF2016-77103-P), from University of Cantabria (Proyectos Puente 2020), and from Instituto de Investigación Sanitaria Valdecilla (IDIVAL) (APG/12)

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

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.This work was supported by grants from the Spanish Economy and Competitiveness Ministry (SAF2016-77103-P) and from Instituto de Investigación Sanitaria Valdecilla (IDIVAL) (APG/12)

Melatonin enhances the apoptotic effects and modulates the changes in gene expression induced by docetaxel in MCF 7 human breast cancer cells

Results from clinical trials and multiple in vivo and in vitro studies point to melatonin as a promising adjuvant molecule with many beneficial effects when concomitantly administered with chemotherapy. Melatonin palliates side?effects and enhances the efficacy of chemotherapeutic agents. However, the mechanisms through which melatonin regulates molecular changes induced by chemotherapeutic agents remain largely unknown. In this study, we demonstrated that melatonin enhanced the anti-proliferative and apoptotic responses to low doses of docetaxel in breast cancer cells. Importantly, these effects were more potent when melatonin was added prior to docetaxel. Treatment with 1 µM docetaxel (equivalent to the therapeutic dosage) induced changes in gene expression profiles and melatonin modulated these changes. Specifically, docetaxel downregulated TP53, cyclin-dependent kinase inhibitor 1A (CDKN1A) and cadherin 13 (CDH13), and upregulated mucin 1 (MUC1), GATA binding protein 3 (GATA3) and c-MYC, whereas melatonin counteracted these effects. Melatonin further stimulated the expression of the pro-apoptotic BAD and BAX genes, and enhanced the inhibition of the anti-apoptotic gene BCL-2 induced by docetaxel. The findings of this study suggest that melatonin is a molecule with potential for use as an adjuvant in cancer chemotherapy, which may have implications for designing clinical trials using chemotherapeutic drugs in combination with melatonin.Acknowledgements: The present study was supported by grants from the Spanish Science Technology and Innovation Ministry (grant no. SAF2016 77103-P) and the Research Institute Valdecilla (grant no. APG/12)

Complementary actions of melatonin on angiogenic factors,the angiopoietin/Tie2 axis and VEGF, in co-cultures of human endothelial and breast cancer cells

Melatonin exerts oncostatic activity in breast cancer through antiangiogenic actions. There, the aim of the present study was to ascertain whether melatonin modulates, in a coordinated action, angiopoietin-1 (ANG-1), ANG-2, their cognate Tie2 receptor and VEGF in co-cultures of human endothelial cells (HUVECs) and breast cancer (MCF-7) cells. To accomplish this we used co-cultures of human breast cancer cells (MCF-7) or non-malignant human mammary epithelial cells (MCF?10A) with endothelial cells (HUVECs). The presence of breast cancer cells increased HUVEC proliferation and 1 mM melatonin prevented this effect. ANG-1, ANG-2 and VEGF levels in co-culture media and mRNA expression were upregulated and Tie2 mRNA expression was downregulated in the HUVECs and MCF-7. Melatonin (1 mM) downregulated ANG-1, ANG-2 and VEGF levels in the co-culture media and mRNA expression in both types of cells and upregulated Tie2 mRNA expression in HUVECs. ANG-1, ANG-2, Tie2 and VEGF mRNA expression were not modified during HUVEC/MCF-10A co-culture. Estradiol (10 nM) increased ANG-1, ANG-2 and VEGF mRNA expression in HUVECs and melatonin (1 mM) counteracted this effect. We conclude that melatonin simultaneously coordinates downregulation of angiopoietins with a reduction in VEGF, which could be an effective therapeutic strategy for blocking tumor angiogenesis.The present study was supported by grants from the Spanish Economy and Competitiveness Ministry (SAF2013-42012-P, SAF2016-77103-P), and from the Instituto de Investigación Sanitaria Valdecilla (IDIVAL) (APG/12)

Experiencias de victimización en mujeres sin hogar del sur de España

The feminisation of poverty has give rise to the number of homeless women. The aim of this work, based on a qualitative research methodology, is to know about the existence of victimisation experiences among the women homeless population both before and during the homeless situation. The results have shown vulnerability and gender´s violence impact on biographical trajectories of the interviewed women. As well, it showed how the sexual vulnerability has a significant presence in the women homelessness experience, being possible understanding that as a real gender particularity.La feminización de la pobreza ha dado lugar a un aumento del número de mujeres sin hogar. El objetivo de este trabajo, basado en una investigación cualitativa, es conocer la presencia de experiencias de victimización en población sin hogar femenino tanto de manera previa a la situación de calle como durante la misma. Los resultados han puesto de manifiesto el impacto que tiene la vulnerabilidad y violencia de género en sus trayectorias biográficas. Asimismo, muestran cómo la vulnerabilidad sexual está muy presente en la experiencia de sinhogarismo femenino entendida como una particularidad de género de esta población

Homeless women in Spain. Narratives about gender, social vulnerability and welfare scheme’s effects

El sinhogarismo femenino representa una problemática dentro del contexto español que requiere ser analizada. En los últimos años, la llamada feminización de la pobreza ha puesto de manifiesto un auge del número de mujeres sin hogar, que hace necesario desarrollar estudios empíricos sobre la cuestión. Por ello, la finalidad de este trabajo basado en una investigación cualitativa ha sido conocer la experiencia femenina del sinhogarismo, tratar de dilucidar el modo en que las violencias sociales y la vulnerabilidad de género se inscriben en las historias de vida de estas mujeres. Del mismo modo, también se ha prestado atención a los efectos del entramado y de la praxis asistencial en la condición del sinhogarismo femenino. Los resultados obtenidos revelan el impacto que tienen las experiencias de victimización en las trayectorias biográficas de las mujeres sin hogar, donde las situaciones de violencia de género y maltrato son recurrentes. Las narrativas de estas mujeres permiten reconocer las carencias del modelo de intervención asistencialista exponiendo los efectos negativos que el entramado asistencial genera.Women´s homelessness represents a problematic needed of an analysis at the Spanish context. Last years the called “feminization of the poverty” has showed an increasing number of women in homeless situation that inform on the necessity of empirical studies about this issue. Therefore the objective of this paper based on a qualitative research, has been to know about the homeless women’s experiences, trying to elucidate the way which social violence and gender´s vulnerability become carved on the life´s stories of these women. Likewise, attention have been paid to the welfare scheme´s and professional praxis´s effects over the women homelessness condition. Obtained results show the victimization experiences impact on the biographical trajectories of the homeless women, which the gender´s violence and abuse situations are recurrent. These women narratives allow us to recognize the lack of the welfare intervention model showing the negative effects generated by the welfare scheme