Atividade citotóxica de vitanolido inédito isolado das folhas da Iochroma arborescens (Solanaceae) em células NCI-H460 e A-549 de câncer de pulmão

Abstract

Lung cancer remains one of the leading causes of cancer mortality worldwide, with significant limitations in current treatments, including resistance to conventional therapies and adverse side effects. In this scenario, the investigation of new therapeutic agents is crucial. Withanolides, which are steroidal lactones present in plants of the Solanaceae family, emerge as promising candidates, standing out for their significant biological activities. This study focused on evaluating the antiproliferative potential of three specific withanolides, the vitafisalinas F, DB74, and W17, isolated from Iochroma arborescens. These compounds showed cytotoxic activity against various tumor cell lines, with vitafisalina DB74, the major compound and isolated for the first time in this study, demonstrating particular efficacy. Analysis of lung cancer cells NCI-H460 and A-549 revealed that treatment with vitafisalina DB74 induced apoptotic features, such as cell retraction, chromatin condensation, and apoptotic body formation. An accumulation of cells in the G2/M phase of the cell cycle was also observed, in addition to a significant increase in apoptosis and necrosis, especially in the A-549 cell line. Molecular docking assays suggested a strong affinity of vitafisalina DB74 for protein kinase C (PKC), indicating the inhibition of this pathway as a potential mechanism for the observed effects. Western blot analyses confirmed a reduction in PKC expression and an increase in phosphorylation of the RAF proto-oncogene serine/threonine-protein kinase (c-RAF) at Ser259, suggesting a negative regulation of c-RAF activity and contributing to the inhibition of the Protein Kinase C/Mitogen-Activated Protein Kinase (PKC/MAPK) signaling pathway. These results suggest that the antiproliferative effect of vitafisalina DB74 may be related, in part, to the inhibition of the PKC/MAPK pathway, through increased phosphorylation of c-RAF at Ser259. The findings indicate that withanolides, especially vitafisalina DB74, have significant potential as new therapeutic agents in the treatment of lung cancer, justifying further investigations to confirm these mechanisms and explore their full therapeutic potential. This study not only highlights the importance of plant biodiversity in the discovery of new anticancer compounds but also the need for more in-depth studies to fully understand the underlying mechanisms of the antitumor activity of withanolides.