ABSTRACT
Breast cancer is a global public health problem and the most frequent cause of cancer death among women. Mammary carcinogenesis is driven not only by genetic alterations but also by epigenetic disturbances. Because epigenetic marks are potentially reversible they represent promising molecular targets for breast cancer prevention interventions. Selenium is a promising anti-breast cancer trace element that has shown the modulation of DNA methylation and histone post-translational modifications in other malignancies. This study aimed to evaluate the effects of selenium compounds [methylseleninic acid (MSA) and selenite] on cell proliferation and death, expression of the tumor suppressor gene RASSF1A and epigenetic marks in MCF-7 human breast adenocarcinoma cells. Treatment with MSA or selenite markedly inhibited (P<0.05) in a dose-dependent manner the proliferation of MCF-7 cells. MSA induced (P<0.05) G2/M cell arrest while selenite presented the opposite effect. Regarding cell death induction, MSA acted mainly by inducing apoptosis (P<0.05), while selenite only induced necrosis (P<0.05). Furthermore selenite, but not MSA, markedly induced (P<0.05) cytotoxicity and increased (P<0.05) RASSF1A expression. Both selenium compounds inhibited (P<0.05) DNMT1 expression. MSA decreased (P<0.05) H3K9me3 and increased (P<0.05) H4K16ac, while selenite decreased (P<0.05) this latter histone mark. To the best of our knowledge this is the first report showing that selenite and MSA modulate epigenetic marks specifically in breast cancer cells. Our data reinforce the anti-breast cancer potential of selenium that is dependent on its chemical form. Furthermore the data show that epigenetic mechanisms represent relevant molecular targets involved in selenium inhibitory effects in breast cancer cells.
Subject(s)
Epigenesis, Genetic/genetics , Selenium Compounds/pharmacology , Apoptosis/drug effects , Breast Neoplasms/genetics , Cell Proliferation/drug effects , Epigenesis, Genetic/drug effects , Female , Humans , MCF-7 Cells , Organoselenium Compounds/pharmacology , Selenious Acid/pharmacology , Tumor Suppressor Proteins/geneticsABSTRACT
The presence of furan in common cooked foods along with evidence from experimental studies that lifetime exposure to furan causes liver tumors in rats and mice has caused concern to regulatory public health agencies worldwide; however, the mechanisms of the furan-induced hepatocarcinogenicity remain unclear. The goal of the present study was to investigate whether or not long-term exposure to furan causes epigenetic alterations in rat liver. Treating of male Fisher 344 rats by gavage 5 days per week with 0, 0.92, 2.0, or 4.4 mg furan/kg body weight (bw)/day resulted in dose- and time-dependent epigenetic changes consisting of alterations in DNA methylation and histone lysine methylation and acetylation, altered expression of chromatin modifying genes, and gene-specific methylation. Specifically, exposure to furan at doses 0.92, 2.0, or 4.4 mg furan/kg bw/day caused global DNA demethylation after 360 days of treatment. There was also a sustained decrease in the levels of histone H3 lysine 9 and H4 lysine 20 trimethylation after 180 and 360 days of furan exposure, and a marked reduction of histone H3 lysine 9 and H3 lysine 56 acetylation after 360 days at 4.4 mg/kg bw/day. These histone modification changes were accompanied by a reduced expression of Suv39h1, Prdm2, and Suv4-20h2 histone methyltransferases and Ep300 and Kat2a histone acetyltransferases. Additionally, furan at 2.0 and 4.4 mg/kg bw/day induced hypermethylation-dependent down-regulation of the Rassf1a gene in the livers after 180 and 360 days. These findings indicate possible involvement of dose- and time-dependent epigenetic modifications in the furan hepatotoxicity and carcinogenicity.
Subject(s)
DNA Methylation/drug effects , Environmental Pollutants/toxicity , Epigenesis, Genetic/drug effects , Furans/toxicity , Liver/drug effects , Animals , DNA Methylation/genetics , Dose-Response Relationship, Drug , Histone-Lysine N-Methyltransferase/genetics , Liver/metabolism , Male , Rats, Inbred F344 , Time FactorsABSTRACT
No presente estudo avaliou-se a atividade quimiopreventiva da vitamina A (VA), tributirina (TB) e/ou 5-azacitidina (5-AzC) quando administradas isoladamente ou em associação na etapa de promoção do modelo de hepatocarcinogênese. Para tanto, ratos Wistar foram submetidos ao modelo do "hepatócito resistente" (HR), que consistiu na aplicação intraperitoneal de uma dose do agente iniciante dietilnitrosamina (DEN, 20 mg/100 g de p.c.), seguida, 2 semanas após, da aplicação de 4 doses consecutivas de 2- acetilaminofluoreno (2-AAF; 2 mg/100 g de p.c.) e de hepatectomia parcial (HP) a 70 POR CENTO, acrescida de 1 dose de AAF (0,5 mg/100 g de p.c.) 4 dias após a cirurgia. Logo após a aplicação do modelo, os animais receberam VA (1 mg/ 100 g de p.c.) em dias alternados, TB (200 mg/ 100 g de p.c.) todos os dias e /ou 5-AzC (0,25 mg/ 100g de p.c.) duas vezes por semana ou, ainda, óleo de milho, maltodextrina e solução salina (grupo controle) durante cinco semanas. De acordo com a análise macroscópica do fígado, e em comparação ao grupo controle, verificou-se que o grupo tratado com TB isoladamente e o grupo tratado com VA e TB em associação apresentaram menor (p < 0,05) incidência e menor (p < 0,05) número médio de nódulos hepáticos. Em relação à análise morfométrica das lesões pré-neoplásicas (LPN) hepáticas positivas para a enzima glutationa S-transferase forma placentária (GST-P), observou-se que em comparação ao grupo controle os grupos experimentais que receberam 5-AzC apresentaram maior (p < 0,05) número de LPN hepáticas totais (persistentes + remodelação), LPN persistentes e LPN em remodelação, indicando que a 5-AzC teve ação potencializadora da iniciação nesse modelo de hepatocarcinogênese. Além disso, quando comparado ao grupo controle, observou-se que o grupo que recebeu TB isoladamente e o grupo que recebeu TB e nos tamanhos das LPN persistentes. Em comparação aos animais do grupo controle, não...
Chemopreventive activity of vitamin A (VA), tributyrin (TB) and/or 5-azacitidine (5-AzC) when administrated isolated or in association, was evaluated during the promotion phase of the "Resistant Hepatocyte"(RH) model of hepatocarcinogenisis. Rats received one dose of diethylnitrosamine (DEN; 20 mg/100g body weigh [b.w.]) for initiation and two weeks later, the animals received five doses of 2-acetylaminofluorene (AAF, 2 mg/100g b.w.), 4 consecutive doses before partial (2/3) hepatectomy and the remaining one four days after surgery. After 3 days, the animals received vitamin A (1mg/100 g.w.), TB (200 mg/ 100g de b.w.) and /or 5-AzC (0,25 mg/ 100 g de b. w.) or corn oil, maltrodextrin and saline (control goup) during five consecutive weeks. Incidence area of visible hepatocyte nodules/animal were smaller (p < 0,05) in goups that received TB and VA +TB than control group. Number of total (persistant + remodeling), persistent and remodeling hepatic placental glutathione S-transferase (GST-P) positive preneoplastic lesions (PNL) were higher (p < 0,05) in groups that received 5-AzC, indicating that 5-AzC potentiates initiation induced by carcinogens in rat liver. Moreover, the groups that received TB isolated or in association with VA presented mean area of persistent hepatic GST-p positive PNL smaller (p < 0,09) than control group. The animals treated with 5-AzC showed higher (p < 0,05) growth index in PNL than control group. The treatment with VA and TB isolated or in association increased (p < 0,05) the number of apoptotic bodies in PNL when compared to control group. Compared to normal group lower (p < 0,05) hepatic concentrations of retinyl palmitate were observed in control group, indicating that VA metabolism is altered in initial phases of hepatocarcinogenesis. The experimental groups that received VA showed higher concentrations of retinol and retinyl palmitate than control group. Moreover, the animals that received TB showed higher concentration...
