title: Synergistic cooperation between ABT-263 and MEK1/2 inhibitor: effect on apoptosis and proliferation of acute myeloid leukemia cells.
abstract: In spite of intensive research to improve treatment of acute myeloid leukemia (AML) more than half of all patients continue to develop a refractory disease. Therefore there is need to improve AML treatment. The overexpression of the BCL-2 family anti-apoptotic members, like BCL-2 or BCL-xL has been largely reported in lymphoid tumors but also in AML and other tumors. To counteract the anti-apoptotic effect of BCL-2, BH3 mimetics have been developed to target cancer cells. An increase in activity of ERK1/2 mitogen activated protein (MAP) kinase has also been reported in AML and might be targeted by MEK1/2 inhibitors. Hence, in the current work, we investigated whether the association of a BH3 mimetic such ABT-263 and the MEK1/2 inhibitor pimasertib (MEKI), was efficient to target AML cells. A synergistic increasing of apoptosis was observed in AML cell lines and in primary cells without affecting normal bone marrow cells. Such cooperation was confirmed on tumor growth in a mouse xenograft model of AML. In addition we demonstrated that MEKI sensitized the cells to apoptosis through its ability to promote a G1 cell cycle arrest. So, this combination of a MAP Kinase pathway inhibitor and a BH3 mimetic could be a promising strategy to improve the treatment of AML.
authors.affiliation: Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux, Bordeaux, France.|CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Pessac, France.
authors.forename: Kelly
authors.initials: K
authors.lastname: Airiau
authors.affiliation: Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux, Bordeaux, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Prouzet-Mauléon
authors.affiliation: Animalerie A2, Université Bordeaux Segalen, Bordeaux, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Rousseau
authors.affiliation: Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux, Bordeaux, France.|CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Pessac, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pigneux
authors.affiliation: CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Pessac, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Jeanneteau
authors.affiliation: CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Pessac, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Giraudon
authors.affiliation: Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux, Bordeaux, France.|CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Pessac, France.
authors.forename: Kaoutar
authors.initials: K
authors.lastname: Allou
authors.affiliation: EA 2406 Histologie et Pathologie, Université Bordeaux, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.affiliation: Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux, Bordeaux, France.|CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Pessac, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Belloc
authors.affiliation: Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux, Bordeaux, France.|CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Pessac, France.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
mesh_terms: D000208:Acute Disease; D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007150:Immunohistochemistry; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D009536:Niacinamide; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C528561:navitoclax
keywords: BH3 mimetic drugs; MEK inhibitors; acute myeloid leukemia