The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells
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PRECLINICAL STUDIES
The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells Małgorzata Opydo-Chanek 1
&
Iwona Cichoń 1 & Agnieszka Rak 2 & Elżbieta Kołaczkowska 1 & Lidia Mazur 1
Received: 4 January 2020 / Accepted: 26 March 2020 # The Author(s) 2020
Summary One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration. Keywords Obatoclax . Differentiation . Apoptosis . Acute myeloid leukemia . HL-60 cells
Abbreviations AML Annexin V-FITC ATRA Bcl-2 Bcl-xL Bcl-w Bax Bak BH DMSO Mcl-1 NBT OBAT
acute myeloid leukemia fluoresceinated annexin V all-trans-retinoic acid B cell lymphoma 2 B cell lymphoma extra-large Bcl-2-like protein 2 Bcl-2-associated X protein Bcl-2-associated killer Bcl-2 homology domain dimethyl sulfoxide myeloid cell leukemia-1 nitro blue tetrazolium obatoclax
* Małgorzata Opydo-Chanek [email protected] 1
Department of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Kraków, Poland
2
Department of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Kraków, Poland
PI PMA
propidium iodide phorbol 12-myristate 13-acetate
Introduction Acute myeloid leukemia (AML) is a hematological malignancy in which the bone marrow is replaced by a clonal population of abnormal myeloid progenitors [1]. The major feature of AML is differentiation arrest of these progenitor cells at early stages of myelopoiesis. This is further accompanied by enhanced cell proliferation and resistance to death-inducing signals. Therefore, AML is a disorder of impaired hematopoietic cell differentiation and apoptosis. Therapies aimed at resuming the process of maturation and apoptosis in leukemic cells are currently the most promising anti-AML strategies [1]. Treatment of acute promyelocytic leukemia (APL), a subty
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