Synergistic cooperation between ABT-263 and MEK1/2 inhibitor: effect on apoptosis and proliferation of acute myeloid leukemia cells
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Kelly Airiau1,2, Valérie Prouzet-Mauléon1, Benoit Rousseau3, Arnaud Pigneux1,2, Marie Jeanneteau2, Manon Giraudon2, Kaoutar Allou1,2, Pierre Dubus4, Francis Belloc1,2,*, François-Xavier Mahon1,2,*
1Laboratoire d’Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux, Bordeaux, France
2CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d’Hématologie, Pessac, France
3Animalerie A2, Université Bordeaux Segalen, Bordeaux, France
4EA 2406 Histologie et Pathologie, Université Bordeaux, Bordeaux, France
*These authors have contributed equally to this work
François-Xavier Mahon, e-mail: [email protected]
Keywords: acute myeloid leukemia, MEK inhibitors, BH3 mimetic drugs
Received: June 28, 2015 Accepted: November 16, 2015 Published: November 27, 2015
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.
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