Browsing by Author "Ferreira, Bibiana"
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- Adaptive mechanisms of resistance to antineoplastic agentsPublication . Ferreira, Bibiana; Lie, Maria K.; Engelsen, Agnete S. T.; Machado, Susana; Link, Wolfgang; Lorens, James B.Intrinsic and acquired resistance to conventional and targeted therapeutics is a fundamental reason for treatment failure in many cancer patients. Targeted approaches to overcome chemoresistance as well as resistance to targeted approaches require in depth understanding of the underlying molecular mechanisms. The anti-cancer activity of a drug can be limited by a broad variety of molecular events at different levels of drug action in a cell-autonomous and non-cell-autonomous manner. This review summarizes recent insights into the adaptive mechanisms used by tumours to resist therapy including cellular phenotypic plasticity, dynamic alterations of the tumour microenvironment, activation of redundant signal transduction pathways, modulation of drug target expression levels, and exploitation of pro-survival responses.
- Comparative complete scheme and booster effectiveness of COVID‐19 vaccines in preventing SARS‐CoV‐2 infections with SARS‐CoV‐2 Omicron (BA.1) and Delta (B.1.617.2) variants: A case–case study based on electronic health recordsPublication . Kislaya, Irina; Peralta‐Santos, André; Borges, Vítor; Vieira, Luís; Sousa, Carlos; Ferreira, Bibiana; Pelerito, Ana; Gomes, João Paulo; Leite, Pedro Pinto; Nunes, Baltazar; Machado, Ausenda; Rodrigues, Ana Paula; Peixoto, Vasco Ricoca; Casaca, Pedro; Fernandes, Eugenia; Rodrigues, Eduardo; Ferreira, Rita; Isidro, Joana; Pinto, Miguel; Duarte, Sílvia; Santos, Daniela; Meneses, Luís; Almeida, José Pedro; Matias, Ana; Freire, Samanta; Grilo, TeresaBackground: Information on vaccine effectiveness in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sub-lineages) VOC according to vaccination exposure (primary or booster). Methods: We developed a case–case study using data on RT-PCR SARS-CoV2-positive cases notified in Portugal during Weeks 49–51, 2021. To obtain measure of comparative vaccine effectiveness, we compared the odds of vaccination in Omicron cases versus Delta using logistic regression adjusted for age group, sex, region, week of diagnosis, and laboratory of origin. Results: Higher odds of vaccination were observed in cases infected by Omicron VOC compared with Delta VOC cases for both complete primary vaccination (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.8 to 2.4) and booster dose (OR = 5.2; 95% CI: 3.1 to 8.8), equivalent to reduction of vaccine effectiveness from 44.7% and 92.8%, observed against infection with Delta, to 6.0% (95% CI: 29.2% to 12.7%) and 62.7% (95% CI: 35.7% to 77.9%), observed against infection with Omicron, for complete primary vaccination and booster dose, respectively. Conclusion: Consistent reduction in vaccine-induced protection against infection with Omicron was observed. Complete primary vaccination may not be protective against SARS-CoV-2 infection in regions where Omicron variant is dominant.
- Decavanadate and metformin-decavanadate effects in human melanoma cellsPublication . de Sousa-Coelho, Ana Luísa; Aureliano, Manuel; Fraqueza, Gil; Serrão, Gisela; Gonçalves, João; Sánchez-Lombardo, Irma; Link, Wolfgang; Ferreira, BibianaDecavanadate is a polyoxometalate (POMs) that has shown extensive biological activities, including antidiabetic and anticancer activity. Importantly, vanadium-based compounds as well as antidiabetic biguanide drugs, such as metformin, have shown to exert therapeutic effects in melanoma. A combination of these agents, the metformin-decavanadate complex, was also recognized for its antidiabetic effects and recently described as a better treatment than the monotherapy with metformin enabling lower dosage in rodent models of diabetes. Herein, we compare the effects of decavanadate and metformin-decavanadate on Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from rabbit skeletal muscles and on cell signaling events and viability in human melanoma cells. We show that unlike the decavanadate-mediated non-competitive mechanism, metformin-decavanadate inhibits Ca2+-ATPase by a mixed-type competitive-non-competitive inhibition with an IC50 value about 6 times higher (87 mu M) than the previously described for decavanadate (15 mu M). We also found that both decavanadate and metformin-decavanadate exert antiproliferative effects on melanoma cells at 10 times lower concentrations than monomeric vanadate. Western blot analysis revealed that both, decavanadate and metformin-decavanadate increased phosphorylation of extracellular signal-regulated kinase (ERK) and serine/ threonine protein kinase AKT signaling proteins upon 24 h drug exposure, suggesting that the anti-proliferative activities of these compounds act independent of growth-factor signaling pathways.
- Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic ShuttlingPublication . Cautain, Bastien; Castillo, Francisco; Musso, Loana; Ferreira, Bibiana; de Pedro, Nuria; Quesada, Lorena Rodriguez; Machado, Susana; Vicente, Francisca; Dallavalle, Sabrina; Link, WolfgangFOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines.
- FOXO family isoformsPublication . Santos, Bruno F; Grenho, Inês; Martel, Paulo; Ferreira, Bibiana; Link, WolfgangFOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.
- mTORC2 Is the major second layer kinase negatively regulating FOXO3 activityPublication . Jimenez, Lucia; Amenabar, Carlos; Mayoral-Varo, Victor; Mackenzie, Thomas A.; Ramos, Maria C.; Silva, Andreia; Calissi, Giampaolo; Grenho, Inês; Blanco-Aparicio, Carmen; Pastor, Joaquin; Megías, Diego; Ferreira, Bibiana; Link, WolfgangForkhead box O (FOXO) proteins are transcription factors involved in cancer and aging and their pharmacological manipulation could be beneficial for the treatment of cancer and healthy aging. FOXO proteins are mainly regulated by post-translational modifications including phosphorylation, acetylation and ubiquitination. As these modifications are reversible, activation and inactivation of FOXO factors is attainable through pharmacological treatment. One major regulatory input of FOXO signaling is mediated by protein kinases. Here, we use specific inhibitors against different kinases including PI3K, mTOR, MEK and ALK, and other receptor tyrosine kinases (RTKs) to determine their effect on FOXO3 activity. While we show that inhibition of PI3K efficiently drives FOXO3 into the cell nucleus, the dual PI3K/mTOR inhibitors dactolisib and PI-103 induce nuclear FOXO translocation more potently than the PI3Kδ inhibitor idelalisib. Furthermore, specific inhibition of mTOR kinase activity affecting both mTORC1 and mTORC2 potently induced nuclear translocation of FOXO3, while rapamycin, which specifically inhibits the mTORC1, failed to affect FOXO3. Interestingly, inhibition of the MAPK pathway had no effect on the localization of FOXO3 and upstream RTK inhibition only weakly induced nuclear FOXO3. We also measured the effect of the test compounds on the phosphorylation status of AKT, FOXO3 and ERK, on FOXO-dependent transcriptional activity and on the subcellular localization of other FOXO isoforms. We conclude that mTORC2 is the most important second layer kinase negatively regulating FOXO activity.
- Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear exportPublication . Jimenez, Lucia; Mayoral‐Varo, Victor; Amenábar, Carlos; Ortega, Judit; Sequeira, João G. N.; Machuqueiro, Miguel; Mourato, Cristiana; Silvestri, Romano; Angeli, Andrea; Carta, Fabrizio; Supuran, Claudiu T.; Megías, Diego; Ferreira, Bibiana; Link, WolfgangChromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin-1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses, for the treatment of cancer, and to overcome therapy resistance. Recently, selinexor has been approved as the first CRM1 inhibitor for the treatment of multiple myeloma, providing proof of concept for this therapeutic option with a new mode of action. However, selinexor is associated with dose-limiting toxicity and hence, the discovery of alternative small molecule leads that could be developed as less toxic anticancer and antiviral therapeutics will have a significant impact in the clinic. Here, we report a CRM1 inhibitor discovery platform. The development of this platform includes reporter cell lines that monitor CRM1 activity by using red fluorescent protein or green fluorescent protein-labeled HIV-1 Rev protein with a strong heterologous nuclear export signal. Simultaneously, the intracellular localization of other proteins, to be interrogated for their capacity to undergo CRM1-mediated export, can be followed by co-culturing stable cell lines expressing fluorescent fusion proteins. We used this platform to interrogate the mode of nuclear export of several proteins, including PDK1, p110 alpha, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110 alpha partially relies on CRM1-dependent nuclear export, TRIB2 is exported from the nucleus in a CRM1-independent manner. Compound screening revealed the striking activity of an organoselenium compound on the CRM1 nuclear export receptor.
- One-minute and green synthesis of magnetic iron oxide nanoparticles assisted by design of experiments and high energy ultrasound: Application to biosensing and immunoprecipitationPublication . Pérez-Beltrán, Christian Hazael; Jose Garcia-Guzman, Juan; Ferreira, Bibiana; Estevez-Hernandez, Osvaldo; Lopez-Iglesias, David; Cubillana-Aguilera, Laura; Link, Wolfgang; Stanica, N.; Rosa Da Costa, Ana; Maria Palacios-Santander, JoseThe present study is focused on the ultrafast and green synthesis, via the co-precipitation method, of magnetic nanoparticles (MNPs) based on iron oxides using design of experiments (DOE) and high energy sonochemical approach, considering two main factors: amplitude (energy) of the ultrasound probe and sonication time. The combination of these techniques allowed the development of a novel one-minute green synthesis, which drastically reduced the amount of consumed energy, solvents, reagents, time and produced residues. This green sonochemical synthesis permitted to obtain mean particle sizes of 11 ? 2 nm under the optimized conditions of amplitude = 40% (2826 J) and time = 1 min. Their composition, structure, size, morphology and magnetic properties were assessed through X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), scanning and transmission electron microscopy (SEM & TEM), and vibrating sample magnetometry (VSM). The characterization results indicate the proper formation of MNPs, and the correct functionalization of MNPs with different coating agents. The functionalized MNPs were used as: i) biosensor, which could detect mercury in water in the range of 0.030?0.060 ppm, and ii) support onto which polyclonal antibodies were anchored and successfully bound to an osteosarcoma cell line expressing the target protein (TRIB2-GFP), as part of an immunoprecipitation assay.
- Retraction note: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKTPublication . Hill, Richard; Madureira, Patricia; Ferreira, Bibiana; Baptista, Ines; Machado, Susana; Colaҫo, Laura; dos Santos, Marta; Liu, Ningshu; Dopazo, Ana; Ugurel, Selma; Adrienn, Angyal; Kiss-Toth, Endre; Isbilen, Murat; Gure, Ali O.; Link, WolfgangThe authors have retracted this article as it has come to their attention that several images were inappropriately processed and duplicated in multiple figures. In particular, the data were duplicated, and in some cases inverted, across several panels in Figures 2c, 2b, 3d and Supplementary Figure 5. Erroneous data were also included in Figure 2e, Supplementary Figure 1 and Supplementary Figure 8. We apologize to the scientific community for any confusion this article may have caused. Richard Hill, Patricia Madureira, Bibiana I. Ferreira, Susana Machado, Ana Dopazo, Selma Ugurel, Endre Kiss-Toth, Murat isbilen and Wolfgang Link agree with this retraction. Inês Baptista, Laura Colaço, Marta dos Santos, Ningshu Liu, Angyal Adrienn and Ali O. Gure have not responded to correspondence from the Publisher about this retraction.
- Screening health-promoting compounds for their capacity to induce the activity of FOXO3Publication . Jimenez, Lucia; Silva, Andreia; Calissi, Giampaolo; Grenho, Inês; Monteiro, Ana Rita; Mayoral-Varo, Victor; Blanco-Aparicio, Carmen; Pastor, Joaquin; Bustos, Victor; Bracher, Franz; Megías, Diego; Ferreira, Bibiana; Link, WolfgangSeveral chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived beta-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).