Cytotoxicity and modes of action of the tetranortriterpenoid meliartenin towards sensitive and multidrug-resistant cancer cells.

CARPINELLA M. C.*; JORAY M.B.; GONZÁLEZ M.L.; TRUCCO L.; PALACIOS S. M.; BOCCO J.L.

Encuentro; COST Action CM1106: "Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells".; 2014

Cancer is one of the leading causes of death worldwide. Despite chemotherapy has improved life expectancy of patients, the toxicity of currently used drugs together with the resistance acquired by cancer cells, make the development of new anticancer agents necessary. In this sense, flora from central Argentina constitutes an inexhaustible source of active principles which can affect the survival of tumor cells. The aim of this study was to evaluate the cytotoxic capacity of 18 compounds with different bioactivities previously obtained in the laboratory from native and naturalized plants of central Argentina. After performing an MTT assay1 against a panel of sensitive and drug-resistant cancer cells including the leukemic cells CCRF-CEM, CEM/ADR5000, K562 and Lucena 1, the lung tumour cell line A549 and the non tumorigenic HEK293T, the tetranortriterpenoid meliartenin (1) (Fig. 1), a novel structure isolated from Melia azedarach2, resulted the most effective. Compound 1 showed a strong cytotoxic activity with IC50 values towards all tested cells, except Lucena 1, in the range of 0.8-10.5 g/ml (1.4-19.7 M). Another three metabolites, 2´,4´-dihydroxychalcone, (Z,Z)-5-(trideca-4,7-dienyl)-resorcinol and 2´,4´-trihydroxy-2´´,2´´-dimethylchromene-(6,7:5´´,6´´)-flavanone (dalenin) also showed significant anti-proliferative activity with IC50s ranging 2.4 to 36.9 g/ml (9.5-145 M). Fig.1. Chemical structure of meliartenin (1). CCRF-CEM and K562 cell lines were selected for further investigating the modes of action underlying the anticancer activity of 1. Flow cytometric DNA content analysis indicated that treatments with 1.25 g/ml of 1 dramatically increased the proportion of CCRF-CEM and K562 cells in the S phase at 48-72 h incubation. A strong induction of apoptosis was subsequently observed. These results demonstrate that exploring the native and naturalized flora from Argentina appears to be a vital strategy for the development of alternative anticancer agents. References 1. Joray, M. B.; González, M. L.; Palacios, S. M.; Carpinella, M. C. Journal of Agricultural and Food Chemistry 2011, 59, 11534. 2. Carpinella, C.; Ferrayoli, C.; Valladares, G.; Defago, M.; Palacios, S. Bioscience, Biotechnology, and Biochemistry 2002, 66, 1731.