Alexandre José da Silva Góes

A dor, fenômeno multifacetado que envolve aspectos sensoriais e emocionais, atua como mecanismo protetor do organismo, normalmente associada a processos de lesão tecidual de origem física ou psicológica. O manejo farmacológico dessa condição abrange diversas classes terapêuticas, cada uma com mecanismos de ação e indicações específicas. Desde os primórdios da humanidade, as plantas medicinais têm sido empregadas para aliviar a dor, tradição que hoje encontra respaldo em estudos científicos capazes de comprovar a eficácia de compostos bioativos. Entre esses, destaca-se a piperina, alcaloide pungente presente na pimenta-preta (Piper nigrum L.), que vem despertando interesse devido ao seu potencial farmacológico no tratamento de diferentes tipos de dor. Nesta revisão, foram consultadas as bases de dados CAPES, SCIELO, BVS e PUBMED, considerando os critérios de inclusão e exclusão, o que resultou na seleção de 18 estudos. As evidências apontam que a piperina possui propriedades analgésicas e anti-inflamatórias, demonstradas tanto em modelos pré-clínicos quanto em ensaios clínicos, com ação ampla em distintos mecanismos de nocicepção. Resultados também indicam efeito sinérgico relevante quando associada à curcumina, potencializando os efeitos terapêuticos. Apesar dos avanços, ainda se faz necessário ampliar o número de pesquisas clínicas para consolidar a aplicação desse composto na prática terapêutica.

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.