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1.
Int J Mol Sci ; 22(21)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34769261

RESUMO

Obesity is a complex disease caused by an excessive amount of body fat. Obesity is a medical problem and represents an important risk factor for the development of serious diseases such as insulin resistance, type 2 diabetes, cardiovascular disease, and some types of cancer. Not to be overlooked are the psychological issues that, in obese subjects, turn into very serious pathologies, such as depression, phobias, anxiety, and lack of self-esteem. In addition to modifying one's lifestyle, the reduction of body mass can be promoted by different natural compounds such as essential oils (EOs). EOs are mixtures of aromatic substances produced by many plants, particularly in medicinal and aromatic ones. They are odorous and volatile and contain a mixture of terpenes, alcohols, aldehydes, ketones, and esters. Thanks to the characteristics of the various chemical components present in them, EOs are used in the food, cosmetic, and pharmaceutical fields. Indeed, it has been shown that EOs possess great antibiotic, anti-inflammatory, and antitumor powers. Emerging results also demonstrate the anti-obesity effects of EOs. We have examined the main data obtained in experimental studies and, in this review, we summarize the effect of EOs in obesity and obesity-related metabolic diseases.

2.
Molecules ; 26(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299603

RESUMO

Today, an improved understanding of cancer cell response to cellular stress has become more necessary. Indeed, targeting the intracellular pro-oxidant/antioxidant balance triggering the tumor commitment to cell demise could represent an advantageous strategy to develop cancer-tailored therapies. In this scenario, the present study shows how the peel extract of mango-a tropical fruit rich in phytochemicals with nutraceutical properties-can affect the cell viability of three colon cancer cell lines (HT29, Caco-2 and HCT116), inducing an imbalance of cellular redox responses. By using hydro-alcoholic mango peel extract (MPE), we observed a consistent decline in thiol group content, which was accompanied by upregulation of MnSOD-a mitochondrial scavenger enzyme that modulates the cellular response against oxidative damage. Such an effect was the consequence of an early production of mitochondrial superoxide anions that appeared after just 30 min of exposure of colon cancer cells to MPE. The effect was accompanied by mitochondrial injury, consisting of the dissipation of mitochondrial membrane potential and a decrease in the level of proteins localized in the mitochondrial membrane-such as voltage-dependent anion-selective channel (VDAC1), mitofilin, and some members of Bcl-2 family proteins (Mcl-1, Bcl-2 and Bcl-XL)-with the mitochondrial release of apoptogenic factors (cytochrome C and AIF). The analysis of the cytotoxic effects exerted by the different constituents of MPE (gallic acid, mangiferin, citric acid, quinic acid, pentagalloyl glucose, and methyl gallate) allowed us to identify those phytochemicals responsible for the observed anticancer effects, sustaining their future employment as chemopreventive or therapeutic agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Mangifera , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Mangifera/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução/efeitos dos fármacos , Extratos Vegetais/química
3.
Int J Mol Sci ; 21(21)2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33143349

RESUMO

Organotin compounds represent potential cancer therapeutics due to their pro-apoptotic action. We recently synthesized the novel organotin ferulic acid derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays anti-tumor properties in colon cancer cells related with autophagic cell death. The purpose of the present study was to elucidate the mechanism of TBT-F action in colon cancer cells. We specifically show that TBT-F-dependent autophagy is determined by a rapid generation of reactive oxygen species (ROS) and correlated with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silencing by RNA interference markedly increased the anti-tumor efficacy of the compound. Moreover, as a consequence of ROS production, TBT-F increased the levels of glucose regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP), two ER stress markers. Interestingly, Grp78 silencing produced significant decreasing effects on the levels of the autophagic proteins p62 and LC3-II, while only p62 decreased in CHOP-silenced cells. Taken together, these results indicate that ROS-dependent ER stress and autophagy play a major role in the TBT-F action mechanism in colon cancer cells and open a new perspective to consider the compound as a potential candidate for colon cancer treatment.


Assuntos
Autofagia , Neoplasias do Colo/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Compostos de Trialquitina/farmacologia , Apoptose , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 2 Relacionado a NF-E2/genética , Células Tumorais Cultivadas
4.
Healthcare (Basel) ; 8(4)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066519

RESUMO

A lifelong adherence to a gluten-free (GF) diet is currently the only treatment for Celiac disease (CD), an autoimmune disorder that arises after gluten ingestion in individuals who are genetically predisposed. The gluten intake exerts toxic effects through several pathways involving gut barrier integrity, intestinal microbiota composition and immune system stimulation. However, despite the great benefit of GF diet for CD patients, its use has been debated. Indeed, individuals who adopt this diet regime may be at risk of nutrient deficiencies. Emerging evidence supports a beneficial effect of a GF diet also for other pathological conditions, including gluten-related disorders (GRD) often associated to CD, such as Non celiac gluten sensitivity (NCGS) and Dermatitis Herpetiforme (DH) as well as Irritable bowel syndrome (IBS) and Diabetes. This suggests a pathogenic role of gluten in these conditions. Despite the growing popularity of GF diet among consumers, to date, there are limited evidences supporting its use for the management of non-celiac diseases. Therefore, in this review, we discuss whether the GF diet could really improve the general quality of life of patients with GRD and non-GRD conditions, keeping in mind its sensorial limitations and nutritional inadequacies. In addition, we discuss the current motivations, leading to the use of a GF diet, despite the inferior quality of GF products respect to those containing gluten.

5.
Brain Sci ; 10(7)2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659996

RESUMO

Celiac Disease (CD) is an immune-mediated disease triggered by the ingestion of wheat gliadin and related prolamins from other cereals, such as barley and rye. Immunity against these cereal-derived proteins is mediated by pro-inflammatory cytokines produced by both innate and adaptive system response in individuals unable to adequately digest them. Peptides generated in this condition are absorbed across the gut barrier, which in these patients is characterized by the deregulation of its permeability. Here, we discuss a possible correlation between CD and Autistic Spectrum Disorder (ASD) pathogenesis. ASD can be induced by an excessive and inappropriate brain opioid activity during the neonatal period. Cereal-derived peptides produced in celiac patients cross the blood-brain barrier and bind to endogenous opioid receptors interfering with neurotransmission and generating deleterious effects on brain maturation, learning and social relations. Moreover, an increase in oxidative stress and a decrease in the antioxidant capacity, as well as an extended mitochondrial impairment in the brain, could represent a possible connection between ASD and CD. Therefore, we critically discuss the proposed relationship between ASD and CD and the possible usefulness of a gluten-free diet in ASD patients.

6.
Int J Mol Sci ; 20(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652569

RESUMO

WIN55,212-2 (WIN) is a synthetic agonist of cannabinoid receptors that displays promising antitumour properties. The aim of this study is to demonstrate that WIN is able to block the migratory ability of osteosarcoma cells and characterize the mechanisms involved. Using wound healing assay and zymography, we showed that WIN affects cell migration and reduces the activity of the metalloproteases MMP2 and MMP9. This effect seemed to be independent of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein involved in tissue remodeling and extracellular matrix deposition. SPARC release was indeed prevented by WIN, and SPARC silencing by RNA interference did not influence the effect of the cannabinoid on cell migration. WIN also increased the release of extracellular vesicles and dramatically upregulated miR-29b1, a key miRNA that modulates cell proliferation and migration. Interestingly, reduced cell migration was observed in stably miR-29b1-transfected cells, similarly to WIN-treated cells. Finally, we show the absence of SPARC in the extracellular vesicles released by osteosarcoma cells and no changes in SPARC level in miR-29b1 overexpressing cells. Overall, these findings suggest that WIN markedly affects cell migration, dependently on miR-29b1 and independently of SPARC, and can thus be considered as a potential innovative therapeutic agent in the treatment of osteosarcoma.


Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Movimento Celular/efeitos dos fármacos , MicroRNAs/genética , Morfolinas/farmacologia , Naftalenos/farmacologia , Osteossarcoma/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Humanos , MicroRNAs/metabolismo , Osteonectina/metabolismo
7.
Antioxidants (Basel) ; 8(10)2019 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-31546694

RESUMO

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.

8.
Cancers (Basel) ; 11(4)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974805

RESUMO

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.

9.
Nutrients ; 10(10)2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30322062

RESUMO

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.


Assuntos
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
10.
Chem Res Toxicol ; 31(4): 201-210, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29513521

RESUMO

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.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Animais , Humanos , NADPH Oxidases/metabolismo , Neoplasias/enzimologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
11.
Nutrients ; 9(9)2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28885570

RESUMO

Litchi is a tasty fruit that is commercially grown for food consumption and nutritional benefits in various parts of the world. Due to its biological activities, the fruit is becoming increasingly known and deserves attention not only for its edible part, the pulp, but also for its peel and seed that contain beneficial substances with antioxidant, cancer preventive, antimicrobial, and anti-inflammatory functions. Although literature demonstrates the biological activity of Litchi components in reducing tumor cell viability in in vitro or in vivo models, data about the biochemical mechanisms responsible for these effects are quite fragmentary. This review specifically describes, in a comprehensive analysis, the antitumor properties of the different parts of Litchi and highlights the main biochemical mechanisms involved.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Frutas/química , Litchi/química , Animais , Antineoplásicos Fitogênicos/química , Alimento Funcional , Humanos , Extratos Vegetais
12.
Nutrients ; 9(5)2017 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-28531110

RESUMO

Historically, Mangifera indica L. cultivations have been widely planted in tropical areas of India, Africa, Asia, and Central America. However, at least 20 years ago its spreading allowed the development of some cultivars in Sicily, an island to the south of Italy, where the favourable subtropical climate and adapted soils represent the perfect field to create new sources of production for the Sicilian agricultural supply chain. Currently, cultivations of Kensington Pride, Keitt, Glenn, Maya, and Tommy Atkins varieties are active in Sicily and their products meet the requirements of local and European markets. Mango plants produce fleshy stone fruits rich in phytochemicals with an undisputed nutritional value for its high content of polyphenolics and vitamins. This review provides an overview of the antioxidant, anti-inflammatory, and anticancer properties of mango, a fruit that should be included in everyone's diet for its multifaceted biochemical actions and health-enhancing properties.


Assuntos
Agricultura , Frutas/química , Mangifera , Valor Nutritivo , Humanos , Sicília
13.
Int J Oncol ; 49(1): 352-60, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27121069

RESUMO

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.


Assuntos
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
14.
Int J Oncol ; 48(3): 1039-44, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26698404

RESUMO

Secreted protein acidic and rich in cysteine (SPARC) is a multi-functional protein which modulates cell-cell and cell-matrix interactions. In cancer cells, SPARC behaves as a tumor promoter in a number of tumors, but it can also act as a tumor suppressor factor. Our previous results showed that the synthetic cannabinoid WIN55,212-2 (WIN), a potent cannabinoid receptor agonist, is able to sensitize osteosarcoma MG63 cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis which is accompanied with endoplasmic reticulum (ER)-stress induction and the increase in autophagic markers. In the present investigation, we studied the role of SPARC in WIN/TRAIL-induced apoptosis demonstrating that WIN increased the level of SPARC protein and mRNA in a time-dependent manner. This event was functional to WIN/TRAIL-dependent apoptosis as demonstrated by RNA interfering analysis which indicated that SPARC-silenced cells were less sensitive to cytotoxic effects induced by the combined treatment. Our experiments also demonstrate that SPARC interacts with caspase-8 thus probably favoring its translocation to plasma membrane and the activation of extrinsic apoptotic pathway. In conclusion, to the best of our knowledge, our results are the first to show that WIN-dependent increase in the level of SPARC plays a critical role in sensitizing osteosarcoma cells to TRAIL action.


Assuntos
Neoplasias Ósseas/metabolismo , Osteonectina/metabolismo , Osteossarcoma/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose , Benzoxazinas/química , Neoplasias Ósseas/patologia , Caspase 8/metabolismo , Morte Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Sobrevivência Celular , Estresse do Retículo Endoplasmático , Inativação Gênica , Humanos , Morfolinas/química , Naftalenos/química , Osteossarcoma/patologia , Domínios Proteicos , Interferência de RNA
15.
Int J Biol Sci ; 10(5): 466-78, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24795528

RESUMO

The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential. Experiments were performed to determine the effects of WIN on proliferation, cell cycle distribution, and programmed cell death in human osteosarcoma MG63 and Saos-2 cells. Results show that WIN induced G2/M cell cycle arrest, which was associated with the induction of the main markers of ER stress (GRP78, CHOP and TRB3). In treated cells we also observed the conversion of the cytosolic form of the autophagosome marker LC3-I into LC3-II (the lipidated form located on the autophagosome membrane) and the enhanced incorporation of monodansylcadaverine and acridine orange, two markers of the autophagic compartments such as autolysosomes. WIN also induced morphological effects in MG63 cells consisting in an increase in cell size and a marked cytoplasmic vacuolization. However, WIN effects were not associated with a canonical apoptotic pathway, as demonstrated by the absence of specific features, and only the addition of TRAIL to WIN-treated cells led to apoptotic death probably mediated by up-regulation of the tumor suppressor factor PAR-4, whose levels increased after WIN treatment, and by the translocation of GRP78 on cell surface.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Proteínas de Choque Térmico/metabolismo , Morfolinas/farmacologia , Naftalenos/farmacologia , Osteossarcoma/fisiopatologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Laranja de Acridina , Apoptose/efeitos dos fármacos , Cadaverina/análogos & derivados , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Osteossarcoma/tratamento farmacológico , RNA Interferente Pequeno/genética
16.
Apoptosis ; 19(6): 1029-42, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24696378

RESUMO

Cannabinoids have been reported to possess anti-tumorigenic activity in cancer models although their mechanism of action is not well understood. Here, we show that the synthetic cannabinoid WIN55,212-2 (WIN)-induced apoptosis in colon cancer cell lines is accompanied by endoplasmic reticulum stress induction. The formation of acidic vacuoles and the increase in LC3-II protein indicated the involvement of autophagic process which seemed to play a pro-survival role against the cytotoxic effects of the drug. However, the enhanced lysosomal membrane permeabilization (LMP) blocked the autophagic flux after the formation of autophagosomes as demonstrated by the accumulation of p62 and LC3, two markers of autophagic degradation. Data also provided evidence for a role for nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in cannabinoid signalling. PPARγ expression, at both protein and mRNA levels, was significantly down-regulated after WIN treatment and its inhibition, either by specific antagonists or by down-regulation via gene silencing, induced effects on cell viability as well as on ER stress and autophagic markers similar to those obtained in the presence of WIN. Moreover, the observation that the increase in p62 level and the induction of LMP were also modified by PPARγ antagonists seemed to indicate that PPARγ down-regulation was crucial to determinate the block of autophagic flux, thus confirming the critical role of PPARγ in WIN action. In conclusion, at our knowledge, our results are the first to show that the reduction of PPARγ levels contributes to WIN-induced colon carcinoma cell death by blocking the pro-survival autophagic response of cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzoxazinas/farmacologia , Neoplasias do Colo/patologia , Morfolinas/farmacologia , Naftalenos/farmacologia , PPAR gama/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Regulação para Baixo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , PPAR gama/genética , Transdução de Sinais/efeitos dos fármacos
17.
Int J Oncol ; 43(1): 121-30, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23686163

RESUMO

Notch is a family of transmembrane receptors whose activation through proteolytic cleavage by γ-secretase targets genes which participate in cell development, differentiation and tumorigenesis. Notch signaling is constitutively activated in various cancers, including breast cancer and its upregulation is usually related with poor clinical outcomes. Therefore, targeting Notch signaling with γ-secretase inhibitors (GSIs) is considered a promising strategy for cancer treatment. We report that the γ-secretase inhibitor-I (GSI-I) sensitizes human breast cancer cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The antiproliferative GSI-I/TRAIL synergism was stronger in ER-negative MDA-MB-231 breast cancer cells compared with ER-positive MCF-7 cells. In MDA-MB-231 cells, GSI-I treatment induced upregulation of DR4 and DR5 TRAIL receptors. This effect seemed to be related to the activation of the transcription factor AP1 that was a consequence of Notch inhibition, as demonstrated by Notch-1 silencing experiments. Combined treatment induced loss of the mitochondrial transmembrane potential and activation of caspases. GSI-I alone and/or GSI-I/TRAIL combination also induced a significant decrease in the levels of some survival factors (survivin, c-IAP-2, Bcl-xL, BimEL and pAKT) and upregulation of pro-apoptotic factors BimL, BimS and Noxa, enhancing the cytotoxic potential of the two drugs. Taken together, these results indicate for the first time that GSI-I/TRAIL combination could represent a novel and potentially effective tool for breast cancer treatment.


Assuntos
Neoplasias da Mama/genética , Genes jun/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/biossíntese , Ligante Indutor de Apoptose Relacionado a TNF/genética , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Diferenciação Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Receptores Notch/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
18.
Blood ; 120(17): 3541-54, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-22955913

RESUMO

In myeloid malignancies, the neoplastic clone outgrows normal hematopoietic cells toward BM failure. This event is also sustained by detrimental stromal changes, such as BM fibrosis and osteosclerosis, whose occurrence is harbinger of a dismal prognosis. We show that the matricellular protein SPARC contributes to the BM stromal response to myeloproliferation. The degree of SPARC expression in BM stromal elements, including CD146(+) mesenchymal stromal cells, correlates with the degree of stromal changes, and the severity of BM failure characterizing the prototypical myeloproliferative neoplasm primary myelofibrosis. Using Sparc(-/-) mice and BM chimeras, we demonstrate that SPARC contributes to the development of significant stromal fibrosis in a model of thrombopoietin-induced myelofibrosis. We found that SPARC deficiency in the radioresistant BM stroma compartment impairs myelofibrosis but, at the same time, associates with an enhanced reactive myeloproliferative response to thrombopoietin. The link betwen SPARC stromal deficiency and enhanced myeloid cell expansion under a myeloproliferative spur is also supported by the myeloproliferative phenotype resulting from the transplantation of defective Apc(min) mutant hematopoietic cells into Sparc(-/-) but not WT recipient BM stroma. Our results highlight a complex influence of SPARC over the stromal and hematopoietic BM response in myeloproliferative conditions.


Assuntos
Medula Óssea/metabolismo , Leucemia Mieloide/genética , Células-Tronco Mesenquimais/metabolismo , Células Mieloides/metabolismo , Osteonectina/genética , Mielofibrose Primária/genética , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Antígeno CD146/genética , Antígeno CD146/metabolismo , Proliferação de Células , Células Cultivadas , Feminino , Expressão Gênica , Humanos , Leucemia Mieloide/induzido quimicamente , Leucemia Mieloide/complicações , Leucemia Mieloide/patologia , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Células Mieloides/efeitos dos fármacos , Células Mieloides/patologia , Osteonectina/deficiência , Osteonectina/metabolismo , Mielofibrose Primária/induzido quimicamente , Mielofibrose Primária/complicações , Mielofibrose Primária/patologia , Trombopoetina/efeitos adversos
19.
Int J Oncol ; 41(2): 407-13, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22614735

RESUMO

In recent years, cannabinoids (the active components of Cannabis sativa) and their derivatives have received considerable interest due to findings that they can affect the viability and invasiveness of a variety of different cancer cells. Moreover, in addition to their inhibitory effects on tumor growth and migration, angiogenesis and metastasis, the ability of these compounds to induce different pathways of cell death has been highlighted. Here, we review the most recent results generating interest in the field of death mechanisms induced by cannabinoids in cancer cells. In particular, we analyze the pathways triggered by cannabinoids to induce apoptosis or autophagy and investigate the interplay between the two processes. Overall, the results reported here suggest that the exploration of molecular mechanisms induced by cannabinoids in cancer cells can contribute to the development of safe and effective treatments in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Canabinoides/farmacologia , Neoplasias/patologia , Animais , Antineoplásicos/uso terapêutico , Canabinoides/uso terapêutico , Sinergismo Farmacológico , Humanos , Neoplasias/tratamento farmacológico
20.
Dalton Trans ; 39(38): 9140-5, 2010 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-20820603

RESUMO

The copper(II) complex of 3,5-bis(2'-pyridyl)-1,2,4-oxadiazole was synthesized and characterized. X-Ray crystallography revealed that the complex consists of a discrete [Cu(3,5-bis(2'-pyridyl)-1,2,4-oxadiazole)(2)(H(2)O)(2)](2+) cation and two ClO(4)(-) anions. The Cu(II) coordination sphere has a distorted octahedral geometry and each ligand chelates the copper ion through the N(4) nitrogen of the oxadiazole ring and the nitrogen of one pyridine moiety. The coordinated water molecules are in cis position and each of them is H-bonded to the 5-pyridyl nitrogen of the oxadiazole ligand and to an oxygen of the perchlorate anion. Biological assays showed that, despite the free ligand not being effective, [Cu(3,5-bis(2'-pyridyl)-1,2,4-oxadiazole)(2)(H(2)O)(2)](2+) reduced the vitality of human hepatoblastoma HepG2 and colorectal carcinoma HT29 cells in a dose- and time-dependent manner. The interaction of the cationic copper complex with native DNA was investigated by variable-temperature UV-vis spectroscopy, circular dichroism, viscosity and gel electrophoresis, indicating that it is a groove binder with binding constant K(b) = 2.2 × 10(4) M(-1).


Assuntos
Cobre/química , DNA/química , Compostos Organometálicos/síntese química , Oxidiazóis/química , Piridinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ligantes , Modelos Moleculares , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia
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