Elizabeth Fernanda de Oliveira Borba

Background/Objectives: β-Lapachone (β-lap) is an o-naphthoquinone with potent antitumor activity. However, its clinical application is hindered by poor solubility and toxicity. Thiosemicarbazone derivatives of β-lap (BV3 and BV5) have demonstrated enhanced selectivity and anticancer efficacy in leukemia cells. Therefore, this study aimed to evaluate the therapeutic potential of these derivatives in solid tumors. Furthermore, the mechanism of tumor cell death, the involvement of protein kinase inhibition, and the toxicogenetic safety of BV3 and BV5 were investigated. Methods: The cytotoxic effects of BV3 and BV5 were assessed in cancer cell lines and a non-cancerous cell line. The compounds were most effective against HeLa (human cervical adenocarcinoma) cells. For that reason, this type of cell was chosen to study how the compounds might cause cell death, using flow cytometry. Kinase inhibition assays were conducted in vitro and in silico, followed by genotoxicity assessments to determine toxicogenetic safety. Results: BV3 and BV5 derivatives significantly inhibited cancer cell proliferation after 72 h, with IC₅₀ values ranging from 2.8 to 36.9 µM. BV3 demonstrated superior selectivity (selectivity index: 15.6) when compared to β-lap (selectivity index: 1.9) in HeLa cells. Morphological changes and flow cytometry analysis revealed features of apoptosis and/or necrosis in HeLa cells treated with the compounds BV3 and BV5. Furthermore, among the kinases tested, BV3 and BV5 were more effective in inhibiting the activity of the protein kinases JAK3 and GSK3β. This result was also confirmed by the in silico studies. Additionally, genotoxicity assays indicated an overall favorable toxicogenetic safety profile; however, BV5 exhibited potential genotoxicity at high concentrations. Conclusions: The findings underscore the anticancer potential of BV3 and BV5 in solid tumors and highlight their mechanism of action, which involves protein kinases. The findings also show that the drugs are selective and relatively safe.

Background: With the COVID-19 pandemic, the need for pharmacological and clinical studies in the search for substances with anti-inflammatory action became evident. To perform a systematic review of randomized controlled trials that evaluated the efficacy and safety of quercetin as a treatment and prevention option for COVID-19 in humans relative to an active comparator, placebo, or standard care alone. Methods: The search for studies was carried out in the following databases: Medline via PubMed, LILACS, Science Direct, Web of Science, and Scopus via Capes periodicals with the descriptors: “Quercetin” AND ''COVID-19” AND “randomized controlled trial”. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Protocol registration number in the PROSPERO database: CRD42022359842, available: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359842.Results: 455 articles were found, and after reading the titles, abstracts, and full text, only 8 randomized clinical trials were included. According to the Cochrane RoB 2 tool, most included studies have some concerns about the risk of bias. The use of quercetin in the treatment and prevention of COVID-19 contributed to the rapid evolution of patients compared to standard treatment and protected them against the development of COVID-19 compared to placebo. No adverse events were reported. Conclusion: It is inferred that drug supplementation with quercetin can help in the treatment and prevention of COVID-19, reducing recovery time, laboratory parameters and symptom manifestation, when compared to standard treatment. Thus, further research is needed to confirm the relationship between quercetin in the immune system and the development of COVID-19 in its most severe form. A systematic review carried out with randomized clinical trials for quercetin in COVID-19 is not yet available in the indexes, and this work is unprecedented.

Internacional Saúde Única (Interface Mundial) (978-65-5941-033-0) - Avaliação Da Toxicidade Aguda Pré-Clínica Do Extrato Hexânico De Croton Heliotropiifolius Kunth

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC₅₀ values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3 c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).