Compounds from Argentinian native plants with the ability to reverse multidrug resistance mediated by P-gp.

LAIOLO, JERÓNIMO; GRAIKIOTI, DAFNI G.; GONZÁLEZ, MARÍA LAURA; VERA A., MARIANO D.; ATHANASSOPOULOS, CONSTANTINOS M.; CARPINELLA MARÍA CECILIA

Coimbra

Simposio; Strategem CA17104 New diagnostic and therapeutic tools againts multidrug resistant tumours; 2022

Permeability glycoprotein (P-gp) is an important ATP-dependent transmembrane transporter whose overexpression leads to low efficiency of numerous chemotherapeutic agents against cancer cells. To date, several substances have been tested as inhibitors of this pump, but none of these have passed phase III clinical trials. This is one of the reasons why natural products and their derivatives have received increasing attention in recent years.New molecules with the ability to reverse multidrug resistance (MDR), mediated by P-gp, have been obtained from native plants from Argentina. The lignan pinoresinol (1), isolated from Melia azedarach and the triterpene betulin (2), isolated from Ligaria cuneifolia, showed by themselves inhibitory properties on P-gp function1,2. In order to identify derivatives with improved activity with respect to these compounds, molecular modelling studies were performed and according to the information obtained, a panel of analogues were synthetized. These compounds were tested against K562 human myelogenous leukemic cells and its overexpressing P-gp counterpart, Lucena 1.The results obtained showed that 8-acetoxypinoresinol, was 64 times more effective than compound 1 according to the minimum effective concentrations (MECs) obtained by the reversal assay (0.11 and 7 μM, respectively) and the doxorubicin (Dox) accumulation assay (0.87 and 56 μM, respectively). On the other hand, Bet-38 and Bet-42 were 4- and 8-times, respectively more active than compound 2 (MECs 0.39 and 0.19 and 1.56 μM, respectively) for increasing the intracellular rhodamine 123 accumulation in Lucena 1. In addition, Bet-38 and Bet-42 were shown to be 2 and 16 times, respectively more effective than the lead molecule (MEC 0.39 μM) in reversing Dox resistance. It should be noted that none of the mentioned compounds enhanced the effect of Dox in the K562 cell line and they even showed the same and/or better level of activity (p > 0.05) than that observed with the reference molecule, verapamil.In conclusion, this work demonstrates the importance of natural products as a source of bioactive molecules and repositions these entities as leading compounds for obtaining derivatives capable of reversing MDR phenotype, mediated by the P-gp protein.