RESUMO
Chronic diseases such as cystic fibrosis, inflammatory bowel diseases, rheumatoid arthritis, and cardiovascular illness have been linked to a decrease in selenium levels and an increase in oxidative stress. Selenium is an essential trace element that exhibits antioxidant properties, with selenocysteine enzymes like glutathione peroxidase being particularly effective at reducing peroxides. In this study, a series of synthetic organoselenium compounds were synthesized and evaluated for their potential antioxidant activities. The new selenohydantoin molecules were inspired by selenoneine and synthesized using straightforward methods. Their antioxidant potential was evaluated and proven using classical radical scavenging and metal-reducing methods. The selenohydantoin derivatives exhibited glutathione peroxidase-like activity, reducing hydroperoxides. Theoretical calculations using Density Functional Theory (DFT) revealed the selenone isomer to be the only one occurring in solution, with selenolate as a possible tautomeric form in the presence of a basic species. Cytocompatibility assays indicated that the selenohydantoin derivatives were non-toxic to primary human aortic smooth muscle cells, paving the way for further biological evaluations of their antioxidant activity. The results suggest that selenohydantoin derivatives with trifluoro-methyl (-CF3) and chlorine (-Cl) substituents have significant activities and could be potential candidates for further biological trials. These compounds may contribute to the development of effective therapies for chronic diseases such cardiovascular diseases.
RESUMO
Breast cancer is one of the leading causes of cancer-related death among females worldwide. A major challenge is to develop innovative therapy in order to treat breast cancer subtypes resistant to current treatment. In the present study, we examined the effects of two Troglitazone derivatives Δ2-TGZ and AB186. Previous studies showed that both compounds induce apoptosis, nevertheless AB186 was a more potent agent. The kinetic of cellular events was investigated by real-time cell analysis system (RTCA) in MCF-7 (hormone dependent) and MDA-MB-231 (triple negative) breast cancer (TNBC) cells, followed by cell morphology analysis by immuno-localization. Both compounds induced a rapid modification of both impedance-based signals and cellular morphology. This process was associated with an inhibition of cell migration measured by wound healing and transwell assays in TNBC MDA-MB-231 and Hs578T cells. In order to identify cytoplasmic targets of AB186, we performed surface plasmon resonance (SPR) and pull-down analyses. Subsequently, 6 cytoskeleton components were identified as potential targets. We further validated α-tubulin as one of the direct targets of AB186. In conclusion, our results suggested that AB186 could be promising to develop novel therapeutic strategies to treat aggressive forms of breast cancer such as TNBC.
Assuntos
Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Tubulina (Proteína)RESUMO
Triple-negative "claudin 1 low" subtype represents around 15% of breast cancer and displays poor prognosis. The loss of claudin 1 is correlated with increased invasiveness and higher recurrence of the disease. Claudin 1 constitutes the backbone of the tight junction and is involved in cell-cell adhesion and migration processes. However, studies showed a controversial role of claudin 1 in cell migration. In this study, we aimed to clarify the effect of claudin 1 on migration of mesenchymal triple-negative breast cancer cells (TNBC). We reported that transient over expression of claudin 1 in MDA-MB-231 and Hs578T "claudin 1 low" TNBC cells inhibited cell migration using wound healing and transwell migration assays. In order to investigate more specifically the involvement of claudin 1, we generated stable MDA-MB-231 clones overexpressing claudin 1. Interestingly, the level of claudin 1 was correlated to the inhibition of cell migration and to the increase of cell-cell aggregation associated with enhanced formation of ß-catenin adherens junction and occludin tight junction. Finally, we reported for the first time the key role of claudin 1 in the inhibition of cell migration process associated with the disappearance of stress fibers. These data suggest that re-expression of claudin 1 could be a promising strategy for regulating the migration of TNBC which no longer express claudin 1.
Assuntos
Movimento Celular , Claudina-1/biossíntese , Proteínas de Neoplasias/biossíntese , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Claudina-1/genética , Feminino , Humanos , Proteínas de Neoplasias/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express claudin-1, a major constituent of tight junction. Patients with these "claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "claudin-1-low" TNBC cells, Δ2-TGZ treatment induced claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced claudin-1 expression in both the cells. In absence of claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that claudin-1 re-expression could be an interesting therapeutic strategy for "claudin-1-low" TNBC.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Claudina-1/metabolismo , Ésteres do Ácido Sulfúrico/farmacologia , Tiazolidinedionas/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Apoptose/genética , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Claudina-1/genética , Feminino , Regulação da Expressão Gênica , Humanos , Transporte Proteico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , TroglitazonaRESUMO
15-Deoxy-∆12,14-prostaglandin J2 (15dPGJ2) is a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that displays anticancer activity. Various studies have indicated that the effects of 15dPGJ2 are due to both PPARγ-dependent and -independent mechanisms. In the present study, we examined the effects of a biotinylated form of 15dPGJ2 (b15dPGJ2) on hormone-dependent MCF7 and triplenegative MDAMB231 breast cancer cell lines. b15dPGJ2 inhibited cell proliferation more efficiently than 15dPGJ2 or the synthetic PPARγ agonist, efatutazone. b15dPGJ2 was also more potent than its non-biotinylated counterpart in inducing apoptosis. We then analyzed the mechanisms underlying this improved efficiency. It was found not to be the result of biotin receptor-mediated increased incorporation, since free biotin in the culture medium did not decrease the anti-proliferative activity of b15dPGJ2 in competition assays. Of note, b15dPGJ2 displayed an improved PPARγ agonist activity, as measured by transactivation experiments. Molecular docking analyses revealed a similar insertion of b15dPGJ2 and 15dPGJ2 into the ligand binding domain of PPARγ via a covalent bond with Cys285. Finally, PPARγ silencing markedly decreased the cleavage of the apoptotic markers, poly(ADP-ribose) polymerase 1 (PARP1) and caspase7, that usually occurs following b15dPGJ2 treatment. Taken together, our data indicate that biotinylation enhances the anti-proliferative and pro-apoptotic activity of 15dPGJ2, and that this effect is partly mediated via a PPARγ-dependent pathway. These results may aid in the development of novel therapeutic strategies for breast cancer treatment.
Assuntos
Neoplasias da Mama/metabolismo , PPAR gama/química , Prostaglandina D2/análogos & derivados , Sítios de Ligação/genética , Biotinilação/métodos , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Modelos Moleculares , Simulação de Acoplamento Molecular , PPAR gama/agonistas , PPAR gama/genética , Prostaglandina D2/química , Prostaglandina D2/farmacologia , Tiazolidinedionas/farmacologiaRESUMO
In Streptomyces ambofaciens, white papillae that genetic instability events generate during aerial mycelium growth, give rise to Pig-pap mutants which are unable to sporulate and devoid of large genome rearrangement. Knowing that genetic and environmental factors can influence the number of papillae per colony, we investigated the effect of nutrient limitated conditions of growth on the formation of white papillae. We observed that under nitrogen limitation and, most particularly, under amino acid limitation, the number of papillae per colony dramatically increased. Most of the Pig-pap mutants deriving from such papillae displayed a mutation in the whiG gene, which encodes the sigma factor sigma(whiG) which is absolutely required for the sporulation process. In most cases, the mutation led to a loss of function. We showed that the Pig-pap mutants deriving from papillae appearing under usual growth conditions also frequently displayed null mutation of whiG too. As the whiG mutation ratio among the Pig-pap mutants isolated with or without nitrogen limited conditions did not change, the results described in this paper suggest that the production of papillae could constitute a response of S. ambofaciens to an amino acid limitation.