L744,832 and Everolimus Induce Cytotoxic and Cytostatic Effects in Non-Hodgkin Lymphoma Cells.

Non-Hodgkin Lymphoma (NHL) constitutes a very heterogeneous group of diseases with different aggressiveness. Diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL) are two clinically aggressive lymphomas from the germinal center, very heterogeneous and with different genetic signatures. Several intracellular pathways are involved in lymphomagenesis, being BCR/PI3K/AKT/mTOR and RAS/RAF pathways the most frequently ones. In this context the therapeutic potential of a mTOR inhibitor--everolimus--and a RAS/RAF pathway inhibitor--L744,832--was evaluated in two NHL cell lines. Farage and Raji cells were cultured in the absence and presence of several concentrations of everolimus and L744,832 in monotherapy and in combination with each other, as well as in association with the conventional chemotherapy drug vincristine. Our results show that everolimus and L744,832 induce antiproliferative and cytotoxic effect in a time-, dose-, and cell line-dependent manner, inducing cell death mainly by apoptosis. A potentiation effect was observed when the drugs were used in combination. In conclusion, the results suggest that everolimus and L744,832, alone or in combination, could provide therapeutic benefits in these subtypes of NHL.