Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer.

The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial-mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis.

New Insights in Radiotherapy.

This Special Issue of , entitled "New insights in Radiotherapy", compiles insightful reviews on the state of the art on different aspects of radiation therapy, and also collects high-quality research articles highlighting the latest advances in the use of ionizing radiation to treat a variety of specific diseases, including cancer, either with curative of palliative purposes [...

Melatonin Modulation of Radiation-Induced Molecular Changes in MCF-7 Human Breast Cancer Cells.

Radiation therapy is an important component of cancer treatment scheduled for cancer patients, although it can cause numerous deleterious effects. The use of adjuvant molecules aims to limit the damage in normal surrounding tissues and enhance the effects of radiation therapy, either killing tumor cells or slowing down their growth. Melatonin, an indoleamine released by the pineal gland, behaves as a radiosensitizer in breast cancer, since it enhances the therapeutic effects of ionizing radiation and mitigates side effects on normal cells.

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.

Melatonin as a Radio-Sensitizer in Cancer.

Radiotherapy is one of the treatments of choice in many types of cancer. Adjuvant treatments to radiotherapy try, on one hand, to enhance the response of tumor cells to radiation and, on the other hand, to reduce the side effects to normal cells. Radiosensitizers are agents that increase the effect of radiation in tumor cells by trying not to increase side effects in normal tissues.

Editorial for the Special Issue "New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies".

The Special Issue entitled "New Strategies in Cancer Pharmacotherapy: Development of Hormonal Antineoplastic Drugs, Cytotoxic Drugs and Targeted Therapies" was conceived with the idea of compiling information on the latest advances in the treatment of both hormone-dependent and hormone-independent cancers [...

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).

Melatonin Modulation of Radiation and Chemotherapeutics-induced Changes on Differentiation of Breast Fibroblasts.

Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the differentiation of breast preadipocytes, by increasing C/EBPα and PPARγ expression and by downregulating tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and IL-11 expression.

Melatonin Enhances the Usefulness of Ionizing Radiation: Involving the Regulation of Different Steps of the Angiogenic Process.

Radiotherapy is a part of cancer treatment. To improve its efficacy has been combined with radiosensitizers such as antiangiogenic agents. Among the mechanisms of the antitumor action of melatonin are antiangiogenic effects.

Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin.

Melatonin mitigates cancer initiation, progression and metastasis through inhibition of both the synthesis of estrogens and the transcriptional activity of the estradiol-ER (Estrogen receptor) complex in the estrogen-dependent breast cancer cell line MCF-7. Moreover, melatonin improves the sensitivity of MCF-7 to chemotherapeutic agents and protects against their side effects. It has been described that melatonin potentiates the anti-proliferative effects of doxorubicin; however, the molecular changes involving gene expression and the activation/inhibition of intracellular signaling pathways remain largely unknown.

Melatonin: An Anti-Tumor Agent in Hormone-Dependent Cancers.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland mainly during the night, since light exposure suppresses its production. Initially, an implication of this indoleamine in malignant disease was described in endocrine-responsive breast cancer. Data from several clinical trials and multiple experimental studies performed both and have documented that the pineal hormone inhibits endocrine-dependent mammary tumors by interfering with the estrogen signaling-mediated transcription, therefore behaving as a selective estrogen receptor modulator (SERM).

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.

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).

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

Vascular endothelial growth factor (VEGF) produced from tumor cells plays a crucial role in the pathogenesis and neovascularization of neuroblastoma. Inhibition of VEGF secretion by tumor cells, as well as VEGF-regulated signaling in endothelial cells, are important to reduce the angiogenesis and growth of neuroblastoma. Since melatonin has anti-angiogenic effects in tumor cell lines, the aim of the present study was to study melatonin modulation of the pro-angiogenic effects of VEGF in neuroblastoma cells (SH-SY5Y).

Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis.

Enhancing the radiosensitivity of cancer cells is one of the most important tasks in clinical radiobiology. Endocrine therapy and radiotherapy are two cancer treatment modalities which are often given together in patients with locally-advanced breast cancer and positive hormone-receptor status. Oncostatic actions of melatonin are relevant on estrogen-dependent mammary tumors.

Melatonin affects the dynamic steady-state equilibrium of estrogen sulfates in human umbilical vein endothelial cells by regulating the balance between estrogen sulfatase and sulfotransferase.

Melatonin is known to reduce the growth of endocrine-responsive breast cancers by interacting with estrogen signaling pathways. Estrogens play an important role in breast cancer, but also in various types of tissues, including vascular tissue. Estrogen sulfatase (STS) converts inactive estrogen sulfates into active estrogens, whereas estrogen sulfotransferase (EST) sulfonates estrogens to estrogen sulfates.

Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair.

Radiation and adjuvant endocrine therapy are nowadays considered a standard treatment option after surgery in breast cancer. Melatonin exerts oncostatic actions on human breast cancer cells. In the current study, we investigated the effects of a combination of radiotherapy and melatonin on human breast cancer cells.

Melatonin modulation of crosstalk among malignant epithelial, endothelial and adipose cells in breast cancer (Review).

Melatonin, the main secretory product of the pineal gland, is an oncostatic agent that reduces the growth and development of various types of tumors, particularly mammary tumors whose growth is dependent on estrogens. Previous and studies point to the hypothesis that melatonin interplays with estrogen signaling pathways at three different levels: i) an indirect mechanism, by interfering with the hypothalamic-pituitary-reproductive axis in such way that the level of plasma estrogens synthesized by the gonadal glands are downregulated; ii) a direct mechanism of the pineal gland at the cell cancer level, disrupting the activation of estradiol receptors, therefore behaving as a selective estrogen receptor modulator; and iii) by regulating the enzymes involved in the biosynthesis of estrogens in other tissues, thus behaving as a selective estrogen enzyme modulator. The intratumoral metabolism and synthesis of estrogens, as a result of the interactions of various enzymes, is more important than blood uptake to maintain mammary gland estrogen levels in menopausal females.

Antiangiogenic effects of melatonin in endothelial cell cultures.

Endothelial cells represent one of the critical cellular elements in tumor microenvironment playing a crucial role in the growth and progression of cancer through controlling angiogenesis. Vascular endothelial growth factor (VEGF) produced from tumor cells is essential for the expansion of breast cancer and may function in both paracrine and autocrine manners to promote proliferation, growth, survival and migration of endothelial cells. Since melatonin regulates tumor microenvironment by decreasing the secretion of VEGF by malignant epithelial cells and also regulates VEGF expression in human breast cancer cells, the aim of the present study was to investigate the anti-angiogenic activity of melatonin against the pro-angiogenic effects of breast cancer cells.

Melatonin modulates aromatase activity and expression in endothelial cells.

Melatonin is known to suppress the development of endocrine-responsive breast cancers by interacting with the estrogen signaling pathways. Paracrine interactions between malignant epithelial cells and proximal stromal cells are responsible for local estrogen biosynthesis. In human breast cancer cells and peritumoral adipose tissue, melatonin downregulates aromatase, which transforms androgens into estrogens.

Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells.

Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen-signaling pathways. Melatonin reduces estrogen biosynthesis in human breast cancer cells, surrounding fibroblasts and peritumoral endothelial cells by regulating cytokines that influence tumor microenvironment. This hormone also exerts antiangiogenic activity in tumoral tissue.

Melatonin interferes in the desmoplastic reaction in breast cancer by regulating cytokine production.

Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen signaling pathways. Melatonin inhibits aromatase enzyme in breast cancer cells and fibroblasts. In addition, melatonin stimulates the adipogenic differentiation of fibroblasts.

Melatonin promotes differentiation of 3T3-L1 fibroblasts.

Melatonin inhibits the genesis and growth of breast cancer by interfering at different levels in the estrogen-signaling pathways. Melatonin inhibits aromatase activity and expression in human breast cancer cells, thus behaving as a selective estrogen enzyme modulator. As the adipose tissue adjacent to the tumor seems to account for most aromatase expression and enzyme activity in breast tumors and also mediates the desmoplastic reaction or accumulation of undifferentiated fibroblasts around malignant epithelial cells, in this work, we studied the effects of melatonin on the conversion of preadipocytes (3T3-L1) into adipocytes and on the capability of these cells to synthesize estrogens by regulating the expression and enzyme activity of aromatase, one of the main enzymes that participates in the synthesis of estrogens in the peritumoral adipose tissue.

In vivo inhibition of the estrogen sulfatase enzyme and growth of DMBA-induced mammary tumors by melatonin.

Melatonin inhibits the growth of different kinds of neoplasias, especially breast cancer, by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces sulfatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. In this study, to investigate the in vivo sulfatase-inhibitory properties of melatonin, this indoleamine was administered to ovariectomized rats bearing DMBA-induced mammary tumors, and treated with estrone sulfate.