title: L744,832 and Everolimus Induce Cytotoxic and Cytostatic Effects in Non-Hodgkin Lymphoma Cells.
abstract: 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.
authors.affiliation: University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine University of Coimbra - FMUC, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Mendes
authors.affiliation: University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine University of Coimbra - FMUC, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|Center of Investigation on Environment Genetic and Oncobiology - CIMAGO, FMUC, Coimbra, Portugal.|Center for Neuroscience and Cell Biology - CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Gonçalves
authors.affiliation: University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine University of Coimbra - FMUC, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|Center of Investigation on Environment Genetic and Oncobiology - CIMAGO, FMUC, Coimbra, Portugal.|Center for Neuroscience and Cell Biology - CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Alves
authors.affiliation: University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine University of Coimbra - FMUC, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|Center of Investigation on Environment Genetic and Oncobiology - CIMAGO, FMUC, Coimbra, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Jorge
authors.affiliation: University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine University of Coimbra - FMUC, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|Center of Investigation on Environment Genetic and Oncobiology - CIMAGO, FMUC, Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Pires
authors.affiliation: University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine University of Coimbra - FMUC, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine University of Coimbra - FMUC, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal. absarmento@fmed.uc.pt.|Center of Investigation on Environment Genetic and Oncobiology - CIMAGO, FMUC, Coimbra, Portugal. absarmento@fmed.uc.pt.|Center for Neuroscience and Cell Biology - CNC.IBILI, University of Coimbra, Coimbra, Portugal. absarmento@fmed.uc.pt.|Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal. absarmento@fmed.uc.pt.
authors.forename: Ana Bela
authors.initials: AB
authors.lastname: Sarmento-Ribeiro
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D054697:Cytostatic Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000068338:Everolimus / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005434:Flow Cytometry; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D004791:Enzyme Inhibitors; D000068338:Everolimus; D051231:Farnesyltranstransferase
keywords: Apoptosis; Burkitt’s lymphoma; Diffuse Large B-cell Lymphoma; Everolimus; L744,832