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Antioxidants (Basel) ; 8(10)2019 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-31546694


Ethanolic extracts from Mangifera indica L. have been proved to possess anti-tumor properties in many cancer systems. However, although most effects have been demonstrated with fruit pulp extract, the underlying molecular mechanisms of mango peel are still unclear. This study was designed to explore the effects of mango peel extract (MPE) on colon cancer cell lines. MPE affected cell viability and inhibited the colony formation trend of tumor cells, while no effects were observed in human dermal fibroblasts used as a non-cancerous cell line model. These events were a consequence of the induction of apoptosis associated to reactive oxygen species (ROS) production, activation of players of the oxidative response such as JNK and ERK1/2, and the increase in Nrf2 and manganese superoxide dismutase (MnSOD). Significantly, mango peel-activated stress triggered a DNA damage response evidenced by the precocious phosphorylation of histone 2AX (γH2AX), as well as phosphorylated Ataxia telangiectasia-mutated (ATM) kinase and p53 upregulation. Mango peel extract was also characterized, and HPLC/MS (High Performance Liquid Chromatography/Mass Spectrometry) analysis unveiled the presence of some phenolic compounds that could be responsible for the anti-cancer effects. Collectively, these findings point out the importance of the genotoxic stress signaling pathway mediated by γH2AX in targeting colon tumor cells to apoptosis.

Cancers (Basel) ; 11(4)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974805


Epidemiological studies suggest that chronic alcohol consumption is a lifestyle risk factor strongly associated with colorectal cancer development and progression. The aim of the present study was to examine the effect of ethanol (EtOH) on survival and progression of three different colon cancer cell lines (HCT116, HT29, and Caco-2). Our data showed that EtOH induces oxidative and endoplasmic reticulum (ER) stress, as demonstrated by reactive oxygen species (ROS) and ER stress markers Grp78, ATF6, PERK and, CHOP increase. Moreover, EtOH triggers an autophagic response which is accompanied by the upregulation of beclin, LC3-II, ATG7, and p62 proteins. The addition of the antioxidant N-acetylcysteine significantly prevents autophagy, suggesting that autophagy is triggered by oxidative stress as a prosurvival response. EtOH treatment also upregulates the antioxidant enzymes SOD, catalase, and heme oxygenase (HO-1) and promotes the nuclear translocation of both Nrf2 and HO-1. Interestingly, EtOH also upregulates the levels of matrix metalloproteases (MMP2 and MMP9) and VEGF. Nrf2 silencing or preventing HO-1 nuclear translocation by the protease inhibitor E64d abrogates the EtOH-induced increase in the antioxidant enzyme levels as well as the migration markers. Taken together, our results suggest that EtOH mediates both the activation of Nrf2 and HO-1 to sustain colon cancer cell survival, thus leading to the acquisition of a more aggressive phenotype.

Nutrients ; 10(10)2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30322062


Litchi chinensis Sonnerat is a tropical tree whose fruits contain significant amounts of bioactive polyphenols. Litchi cultivation has recently spread in Sicily where the climate conditions are particularly favorable for this crop. Recent findings have shown that Litchi extracts display anti-tumor and pro-apoptotic effects in vitro, but the precise underlying mechanisms have not been fully elucidated. In this study, we report for the first time the effects of Sicilian litchi fruit extracts on colon cancer cells. The results indicated that litchi exocarp, mesocarp and endocarp fractions reduce the viability and clonogenic growth of HT29 cells. These effects were due to cell cycle arrest in the G2/M phase followed by caspase-dependent cell death. Interestingly, litchi exocarp and endocarp triggered a precocious autophagic response (16⁻24 h), which was accompanied by an increase in the level of autophagy related 1/autophagy activating kinase 1 (ATG1/ULK1), beclin-1, microtubule associated protein 1 light chain 3 (LC3)-II and p62 proteins. Autophagy inhibition by bafilomycin A1 or beclin-1 silencing increased cell death, thus suggesting that autophagy was initially triggered as a pro-survival response. Significant effects of Litchi extracts were also observed in other colon cancer cells, including HCT116 and Caco-2 cells. On the other hand, differentiated Caco-2 cells, a model of human enterocytes, appeared to be insensitive to the extracts at the same treatment conditions. High-Performance Liquid Chromatography⁻Electrospray Ionization-Quadrupole-Time-Of-Flight HPLC/ESI/Q-TOF evidenced the presence of some polyphenolic compounds, specifically in exocarp and endocarp extracts, that can account for the observed biological effects. The results obtained suggest a potential therapeutic efficacy of polyphenolic compounds purified from Sicilian Litchi fractions for the treatment of colon cancer. Moreover, our findings indicate that modulation of autophagy can represent a tool to improve the effectiveness of these agents and potentiate the anti-tumor response of colon cancer cells.

Antineoplásicos Fitogênicos/uso terapêutico , Apoptose , Autofagia , Neoplasias do Colo/tratamento farmacológico , Litchi/química , Fitoterapia , Polifenóis/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Células CACO-2 , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Frutas/química , Células HT29 , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polifenóis/farmacologia , Sicília , Transdução de Sinais
Chem Res Toxicol ; 31(4): 201-210, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29513521


The intracellular redox state in the cell depends on the balance between the level of reactive oxygen species (ROS) and the activity of defensive systems including antioxidant enzymes. This balance is a dynamic process that can change in relation to many factors and/or stimuli induced within the cell. ROS production is derived from physiological metabolic events. For instance, mitochondria represent the major ROS sources during oxidative phosphorylation, but other systems, such as NADPH oxidase or specific enzymes in certain metabolisms, may account for ROS production as well. Whereas high levels of ROS perturb the cell environment, causing oxidative damage to biological macromolecules, low levels of ROS can exert a functional role in the cell, influencing the activity of specific enzymes or modulating some intracellular signaling cascades. Of particular interest appears to be the role of ROS in tumor systems not only because ROS are known to be tumorigenic but also because tumor cells are able to modify their redox state, regulating ROS production to sustain tumor growth and proliferation. Overall, the scope of this review was to critically discuss the most recent findings pertaining to ROS physiological roles as well as to highlight the controversial involvement of ROS in tumor systems.

Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Animais , Humanos , NADPH Oxidases/metabolismo , Neoplasias/enzimologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
Int J Oncol ; 49(1): 352-60, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27121069


Breast cancer stem cells seem to play important roles in breast tumor recurrence and endocrine therapy resistance, although the underlying mechanisms have not been well established. Moreover, in some tumor systems the immunosurveillance failure against cancer cells has been related to the presence of the granzyme B inhibitor PI-9. This study explored the status of PI-9 in tumorspheres isolated from estrogen receptor-α positive (ERα+) breast cancer MCF7 cells. Studies were performed in tertiary tumorspheres which possess high levels of stemness markers (Nanog, Oct3/4 and Sox2) and self-renewal ability. The exposure to estrogens (17-ß estradiol and genistein) increased the number and sizes of tumorspheres, promoting cell proliferation as demonstrated by the increase in the proliferating cell nuclear antigen (PCNA). The study of the three isoforms (66, 46 and 36 kDa) of ERα disclosed that tertiary tumorspheres exhibit a marked increase in ERα36, while the level of ERα66, which is highly expressed in MCF7 cells, declines. Although it is known that PI-9 is a transcriptional target of ERα66, surprisingly in tertiary tumorspheres, despite the reduced level of ERα66, the protein and mRNA content of PI-9 is higher than in MCF7 cells. Treatment with estrogens further increased PI-9 level while decreased that of ERα66 isoform thus excluding the involvement of this receptor isoform in the event. Moreover, our studies also provided evidence that tertiary tumorspheres express elevated levels of CXCR4 and phospho-p38, suggesting that the high PI-9 content might be ascribed to the activation of the proliferative CXCR4/phospho-p38 axis. Taken together, these events could supply a selective advantage to breast cancer stem cells by interfering with immunosurveillance systems and open up the avenue to new possible targets for breast cancer treatment.

Neoplasias da Mama/genética , Receptor alfa de Estrogênio/biossíntese , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas/metabolismo , Serpinas/biossíntese , Neoplasias da Mama/patologia , Proliferação de Células/genética , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genisteína/administração & dosagem , Granzimas/antagonistas & inibidores , Humanos , Células MCF-7 , Recidiva Local de Neoplasia/fisiopatologia , Células-Tronco Neoplásicas/patologia , Receptores CXCR4/biossíntese , Serpinas/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese