title: Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma.
abstract: Apoptosis plays an important role in the treatment of cancer, and targeting apoptosis-related molecules in ovarian cancer (OC) is of great therapeutic value. Melatonin (Mel) is an indoleamine displaying several anti-cancer properties and has been reported to modulate apoptosis signaling in multiple tumor subtypes. We investigated OC and the role of Mel therapy on the pro-apoptotic (p53, BAX, caspase-3, and cleaved caspase-3) and anti-apoptotic (Bcl-2 and survivin) proteins in an ethanol (EtOH)-preferring rat model. To induce OC, the left ovary was injected directly with a single dose of 100 μg 7,12-dimethylbenz(a)anthracene dissolved in 10 μl of sesame oil under the bursa. Right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of Mel (200 μg/100 g BW per day) for 60 days. Body weight gain, EtOH consumption, and energy intake were unaffected by the treatments. Interestingly, absolute and relative OC masses showed a significant reduction after Mel therapy, regardless of EtOH consumption. To accomplish OC-related apoptosis, we first observed that p53, BAX, caspase-3, and cleaved caspase-3 were downregulated in OC tissue while Bcl-2 and survivin were overexpressed. Notably, Mel therapy and EtOH intake promoted apoptosis along with the upregulation of p53, BAX, and cleaved caspase-3. Fragmentation of DNA observed by TUNEL-positive nuclei was also enhanced following Mel treatment. In addition, Bcl-2 was downregulated by the EtOH intake and lower survivin levels were observed after Mel therapy. Taken together, these results suggest that Mel induce apoptosis in OC cells of EtOH-preferring animals.
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil chuffa@ibb.unesp.br.
authors.forename: Luiz Gustavo A
authors.initials: LG
authors.lastname: Chuffa
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil.
authors.forename: Michelly S
authors.initials: MS
authors.lastname: Alves
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil.
authors.forename: Isabel Cristina C
authors.initials: IC
authors.lastname: Camargo
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil.
authors.forename: Patricia F F
authors.initials: PF
authors.lastname: Pinheiro
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil.
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Domeniconi
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil.
authors.forename: Luiz Antonio L
authors.initials: LA
authors.lastname: Júnior
authors.affiliation: Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil.
authors.forename: Francisco Eduardo
authors.initials: FE
authors.lastname: Martinez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C516989:Birc5 protein, rat; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D008550:Melatonin
keywords: anti-apoptotic protein; melatonin; ovarian cancer; pro-apoptotic protein