title: Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.
abstract: As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.
authors.affiliation: Department of Biology, Universidade Estadual Paulista, São José do Rio Preto, São Paulo, Brazil ; Laboratório de Investigação Molecular no Câncer, Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil.
authors.forename: Bruna Victorasso
authors.initials: BV
authors.lastname: Jardim-Perassi
authors.affiliation: Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
authors.affiliation: Department of Biology, Universidade Estadual Paulista, São José do Rio Preto, São Paulo, Brazil ; Laboratório de Investigação Molecular no Câncer, Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil.
authors.forename: Lívia Carvalho
authors.initials: LC
authors.lastname: Ferreira
authors.affiliation: Laboratório de Investigação Molecular no Câncer, Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil ; Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil.
authors.forename: Thaiz Ferraz
authors.initials: TF
authors.lastname: Borin
authors.affiliation: Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Nadimpalli R S
authors.initials: NR
authors.lastname: Varma
authors.affiliation: Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: A S M
authors.initials: AS
authors.lastname: Iskander
authors.affiliation: Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Shankar
authors.affiliation: Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Meser M
authors.initials: MM
authors.lastname: Ali
authors.affiliation: Laboratório de Investigação Molecular no Câncer, Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil ; Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil.
authors.forename: Debora Aparecida Pires
authors.initials: DA
authors.lastname: de Campos Zuccari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D014841:von Willebrand Factor; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; D008550:Melatonin