Study of the reversal of multidrug resistance by compounds obtained from native and naturalized plants of central Argentina: binding mode of pinoresinol to P-glycoprotein.

CARPINELLA M. C.*; GONZÁLEZ M.L.; D. MARIANO A. VERA; MACCIONI M.; PALACIOS S. M.; RUMJANEK VIVIAN

Encuentro; Meet the Experts 2014; 2014

Multidrug resistance (MDR) is one of the major barrier to successful chemotherapy. The MDR mechanism of major clinical importance results from over-expression of the plasma membrane pump P-glycoprotein (P-gp) which extrudes chemotherapeutic agents out of cells thus, reducing their intracellular concentration and hence the cytotoxicity. This fact has prompted the interest of many researchers to develop inhibitors of P-gp mediated efflux as a way of overcoming MDR in human cancers. In this situation, metabolites biosynthesized by plants become promising candidates to arise as P-gp modulators. Fifteen compounds with different bioactivities previously obtained in the laboratory from native and naturalized plants of central Argentina were tested for their capacity of reversing P-gp mediated chemotherapeutic efflux in the MDR derivative of K562 cells, Lucena 1. After performing MTT assay and the measurement of doxorubicin (DOX) intracellular accumulation by flow cytometry, the compounds ()pinoresinol (1) (Fig. 1), obtained from ethanolic extract of Melia azedarach 1, and dalenin (2) (Fig.1), a novel molecule isolated from Dalea elegans 2, were the most active, being the first the most potent. At 40 g/ml, 1 decreased 9.4 times the IC50 of DOX in Lucena 1 cells and enhanced the uptake of the cytotoxic, reaching those values observed in K562. Compound 1 showed the same level of effectiveness as verapamil, used as reference drug. Docking studies showed that pinoresinol binds to different aromatic residues participating in the "v" vortex involving the trans-membrane -helices 4, 5 and 6, in the same region where powerful known inhibitors, such as tariquidar, were found to bind to 3. The results suggest that compound 1 has great potential to be further developed as a P-gp inhibitor. Fig.1. Chemical structures of ()pinoresinol (1) and dalenin (2). References 1. Carpinella, M. C.; Giorda, L. M.; Ferrayoli, C. G.; Palacios, S. M. Journal of Agricultural and Food Chemistry 2003, 51, 2506. 2. Chiari, M. E.; Vera, D. M. A.; Palacios, S. M.; Carpinella, M. C. Bioorganic & Medicinal Chemistry 2011, 19, 3474. 3. Jara, G. E.; Vera, D. M. A.; Pierini, A. B. J. Mol. Graph. Modeling 2013, 46, 10.