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Oncotarget ; 7(1): 845-59, 2016 Jan 05.
Article in English | MEDLINE | ID: mdl-26625317

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.


Subject(s)
Aniline Compounds/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Niacinamide/analogs & derivatives , Sulfonamides/pharmacology , Acute Disease , Aniline Compounds/administration & dosage , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Synergism , G1 Phase Cell Cycle Checkpoints/drug effects , HL-60 Cells , Humans , Immunohistochemistry , Leukemia, Myeloid/drug therapy , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/pathology , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Niacinamide/administration & dosage , Niacinamide/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Sulfonamides/administration & dosage , Tumor Burden/drug effects , U937 Cells , Xenograft Model Antitumor Assays
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