Percorrer por autor "Carreira, Maria Carolina Lareiro"
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- Evaluation of the Permeability of Brain Barriers to Compounds with Anticancer PropertiesPublication . Carreira, Maria Carolina Lareiro; Duarte, Ana Catarina Abreu; Santos, Cecília Reis Alves dosBrain tumors remain one of the most aggressive and lethal forms of cancer, posing significant challenges to treatment due to their critical location, infiltrative nature, and resistance to conventional therapies. One of the main factors limiting the effectiveness of treatment in brain tumors is the difficulty of chemotherapeutic agents reaching the central nervous system in adequate concentrations. Brain barriers, despite being essential for central nervous system protection and homeostasis, have a high selective nature that restricts the ability of chemotherapeutic agents to reach tumors, reducing the available therapeutic options. This restricted permeability is mostly mediated by the ABC transporter superfamily, which is expressed in both the blood-brain barrier and the blood–cerebrospinal fluid barrier and actively extrudes a wide variety of substances out of the brain, including many anticancer compounds. Taste receptors, traditionally associated with oral cavities, are also expressed in extraoral tissues, including the brain and many tumors. Lactisole, a well-known inhibitor of sweet taste receptors, affects cancer cell proliferation, possibly due to the high glucose dependency of these cells. Quercetin, a bitter compound that is a known ligand of TAS2R14, has demonstrated potential therapeutic effects by overcoming chemoresistance mechanisms and inducing apoptosis in cancer cells. This study aimed to investigate the permeability of the blood-brain and blood– cerebrospinal fluid barriers to lactisole and quercetin, and whether quercetin's interaction with TAS2R14 affects ABC transporter expression. For that a human choroid plexus papilloma cell line (HIBCPP) and a human cerebral microvascular endothelial cell line (hCMEC/D3) were used to establish in vitro models that mimics the in vivo phenotypic characteristics of the blood–cerebrospinal fluid barrier and the blood-brain barrier, respectively. It was verified that lactisole did not reduce viability in the HIBCPP cell line but in hCMEC/D3 cells, a decrease in viability was observed. Through transepithelial electrical resistance measurements and immunocytochemistry, it was possible to optimize the blood-brain barrier model. The 6th day of culture proved to be the most appropriate for the permeability assays, presenting the highest integrity of the cell monolayer and the highest levels of TAS2R14 expression. Additionally, RT-PCR was performed to confirm TAS2R14 expression in both cell lines. The permeability of the barriers to quercetin was not determined, due to completely degradation after 3 hours. Nevertheless, the expression levels of ABCC1 and ABCC4 were assessed in the blood–cerebrospinal fluid barrier cell line following TAS2R14 knockout and subsequent exposure to quercetin. However, no alterations in ABCC1 and ABCC4 expression in mock or TAS2R14 silenced conditions were detected. Lastly, lactisole permeability was assessed in the blood–cerebrospinal fluid barrier model, and a threefold higher concentration was observed in the apical compartment after 4 hours. Thus, it was concluded that lactisole crosses the blood–cerebrospinal fluid barrier in a timedependent manner.