title: Demethylating and anti-hepatocarcinogenic potential of hesperidin, a natural polyphenol of Citrus juices.
abstract: Hepatocellular carcinoma (HCC) is a neoplasia representing the fifth most common malignancy worldwide and the third cause of death from cancer. Diets with high content in fruits and vegetables are widely recommended for their health-promoting properties, among them, the protection against diabetes, cancer, and cardiovascular diseases. Hesperidin is the most important phenol in the orange fruit with well-known health benefits. Diet components have been used as possible modulator agents of DNA methylation in cancer cells and epigenetic therapy against their harmful effects could be a potential tool in chemotherapy. The purpose of the present study was to evaluate the methylation patterns induced by hesperidin in HL60 cell line as an in vitro model in order to analyze its chemopreventive effects in epigenetic cancer therapies. A parallel in vivo pilot experience using a rat diethyl nitrosamine hepatocarcinogenesis-induced model was carried out to validate the therapeutic efficacy of this orange flavonol. Results showed that: (i) Hesperidin is cytotoxic in a dose-dependent manner and the IC50was 12.5 mM; (ii) Hesperidin exerts a significant hypomethylating effect on the LINE-1 sequence (up to 47% hypomethylation at 12.5 mM) and on the ALU-M2 repetitive sequences (up to 32% at 6 mM) in HL60 tumor cells. (iii) Hesperidin does not affect the rat body and liver weight and it is able to reduce the diethyl nitrosamine-induced nodules at 1,000, 500, and 250 ppm. In conclusion, hesperidin could be proposed as a candidate molecule in chemoprevention in epigenetic therapy purposes.
authors.affiliation: Department of Genetics, Campus Rabanales, University of Cordoba, Cordoba, Spain.
authors.forename: Zahira
authors.initials: Z
authors.lastname: Fernández-Bedmar
authors.affiliation: Department of Genetics, Campus Rabanales, University of Cordoba, Cordoba, Spain.
authors.forename: Jaouad
authors.initials: J
authors.lastname: Anter
authors.affiliation: Department of Genetics, Campus Rabanales, University of Cordoba, Cordoba, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Alonso-Moraga
authors.affiliation: Department of Comparative Pathology, Campus Rabanales, University of Cordoba, Cordoba, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Martín de Las Mulas
authors.affiliation: Department of Comparative Pathology, Campus Rabanales, University of Cordoba, Cordoba, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Millán-Ruiz
authors.affiliation: Department of Comparative Pathology, Campus Rabanales, University of Cordoba, Cordoba, Spain.|Department of Oncology, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Cordoba, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guil-Luna
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000032:analysis / Q000627:therapeutic use*; D000975:Antioxidants; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002957:Citrus / Q000737:chemistry; D019175:DNA Methylation / Q000187:drug effects*; D000067030:Fruit and Vegetable Juices / Q000032:analysis*; D006569:Hesperidin / Q000032:analysis / Q000627:therapeutic use*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D017207:Rats, Sprague-Dawley
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D006569:Hesperidin
keywords: DNA methylation; HL60 cell line; diethylnitrosamine; hepatocarcinogenesis; hesperidin