Bioactive compounds isolated from the native and naturalized flora of central Argentina as potential antitumoral agents.

JORAY M; TRUCCO L; GONZÁLEZ M; BOCCO J; RUMJANEK V; CARPINELLA M

Rio de Janeiro

Simposio; VIII Simpósio de Oncobiologia.; 2014

Introduction and aims: Plants represent a valuable source of biologically active compounds. In fact, approximately one-third of the top-selling drugs have been derived from plant ingredients. Although many plant families are being studied, the plant world is far from being totally explored and this also applies to the native flora from Argentina. In this context, eighteen compounds belonging to different chemical families and showing different bioactivities were obtained in our laboratory from native and naturalized plants from Argentina: 23-methyl-6-O-desmethylauricepyrone (1), quercetin (2), 3-O-methylquercetin (3), pinocembrin (4), isoliquiritigenin (5), 7-hydroxyflavanone (6), 7,4´-dihydroxy-3´-methoxyflavanone (7), 2´,4´-dihydroxychalcone (8), (Z,Z)-5-(trideca-4,7-dienyl)-resorcinol (9), 5,2´,4´-trihydroxy-2´´,2´´-dimethylchromen-(6,7:5´´,6´´)-flavanone (10), naringenin (11), apigenin (12), scopoletin (13), ilicol (14), vanillin (15), 3-methoxy-4-hydroxycinnamaldehyde (16), pinoresinol (17) and meliartenin (18). The cytotoxic effect of these metabolites against the tumoral cells CCRF-CEM and CEM/ADR5000 (Acute Linfoblastic Leukemia); K562 and Lucena 1 (Chronic Mieloid Leukemia), A549 (Lung Cancer) and the non tumoral cell line HEK293T, was evaluated. Materials and Methods: The cytotoxic effect of the isolated compounds was evaluated by MTT assay and the correspondig IC50 values were determined. The most active compounds were selected for further studies on K562 and CCRF-CEM cells. The antiproliferative effect was determined by the trypan blue dye exclusion method. Cell cycle distribution analysis and assessment of apoptosis by Propidium iodide (PI) and Annexin V/PI double staining, respectively, were analyzed by flow cytometry. Results: Among the evaluated compounds, 2´,4´-dihydroxychalcone (8) and meliartenin (18), showed the highest cytotoxic effect. Chalcone 8 showed a strong inhibitory effect against CCRF-CEM and CEM/ADR5000 (IC50 = 1.6 and 2.4 g/ml, respectively) and a moderate activity against K562 and Lucena 1 (IC50 = 6.6 and 7.4 g/ml, respectively). It induced a dose and time dependent growth inhibition. Treatments of CCRF-CEM with 8 resulted in an accumulation of cells in G2/M phase, while K562 cells showed a significant increase in the proportion of cells in S and G2/M phases. Annexin V staining showed that this compound induced apoptosis on both cell lines. On the other hand, meliartenin (18) evidenced a strong cytotoxic activity against all the evaluated cell lines (IC50 = 0.8 ? 5.3 g/mL) except for a moderate activity against CEM/ADR5000 (IC50 = 10.5 g/mL) and a nule effect toward Lucena 1 (IC50 > 40 g/mL). Its antiproliferative activity was associated with a strong S-phase cell cycle arrest, accompanied by apoptosis over K562 and CCRF-CEM cells. Conclusions: As far as we know there are no previous reports of the activity of 8 toward these leukemic cell lines. Moreover, this is the first time that the anti-neoplastic activity of 18 is reported. This resulting information suggests that compounds 8 and 18 have a great potential to be further developed into promising antitumoral drugs.