Avaliação da atividade antiproliferativa e da inibição das topoisomerases por extratos, substâncias puras e semi-sintéticas obtidas de produtos naturais

Abstract

DNA topoisomerases are classes of enzymes that control DNA topology. Because their expression is 25 to 300 fold higher in tumor tissues, they are valuable targets for the development of anti-cancer drugs. A number of important anticancer chemotherapeutic agents capable of inhibiting topoisomerases I and II are derived from plants. The purpose of this study was to evaluate the antiproliferative activity of extracts and pure compounds obtained from the species Combretum laxum, Hyptis crenata, Ocotea lancifolia, Aiouea trinervis, Guarea kunthiana, Nymphaea amazonum, Galianthe thalictroides, Pogonopus tubulosus, and Parmotrema lichexantonicum, as well as to assess their inhibitory activity on human topoisomerases I and II and determine selectivity indices against neoplastic cells. Cytotoxicity tests based on sulforhodamine B dye were performed on 9 lines of neoplastic cells and 2 lines of normal cells. The compounds obtained from Combretum laxum roots exhibited potent antiproliferative activity against breast cells (MCF-7). Methoxycoelonin proved more selective against human melanoma cells. Carnosic acid and carnosolic acid isolated from Hyptis crenata showed moderate activity and selectivity against B16-F10 cells. RC6-2 and RC6-5, two alkaloids from Galianthe thalictroides, exhibited potent activity against the MCF-7 and B16-F10 cell lines, as did fraction 6 of the original extract. Topoisomerase-inhibiting activity was assessed in extracts, fractions, and pure compounds with TGI values lower than 30 g/mL. Topoisomerase II was totally inhibited by xantone 17 and alkaloids β-carboline RC6-2 and RC6-5 (100 μM) and partially inhibited by xantone 15 and 16 (200 μM), methoxycoelonina (CP8), carnosolic acid, and the alkaloid PGC12 (100 μM). Topoisomerase I was inhibited by alkaloids β-carboline RC6-2 and RC6-5, pisiferic acid, and xantone 17. These results indicate that the potent cytotoxicity detected is mediated by topoisomerase inhibition, a feature that renders these compounds suitable candidates for cancer treatment trials.