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The Pan-Bcl-2 Inhibitor Obatoclax Promotes Differentiation and Apoptosis of Acute Myeloid Leukemia Cells

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The Pan-Bcl-2 Inhibitor Obatoclax Promotes Differentiation and Apoptosis of Acute Myeloid Leukemia Cells Investigational New Drugs https://doi.org/10.1007/s10637-020-00931-4 PRECLINICAL STUDIES The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells Małgorzata Opydo-Chanek1 & Iwona Cichoń1 & Agnieszka Rak2 & Elżbieta Kołaczkowska1 & 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 PI propidium iodide AML acute myeloid leukemia PMA phorbol 12-myristate 13-acetate Annexin V-FITC fluoresceinated annexin V ATRA all-trans-retinoic acid Bcl-2 B cell lymphoma 2 Introduction Bcl-xL B cell lymphoma extra-large Bcl-w Bcl-2-like protein 2 Acute myeloid leukemia (AML) is a hematological malignan- Bax Bcl-2-associated X protein cy in which the bone marrow is replaced by a clonal popula- Bak Bcl-2-associated killer tion of abnormal myeloid progenitors [1]. The major feature of BH Bcl-2 homology domain AML is differentiation arrest of these progenitor cells at early DMSO dimethyl sulfoxide stages of myelopoiesis. This is further accompanied by en- Mcl-1 myeloid cell leukemia-1 hanced cell proliferation and resistance to death-inducing sig- NBT nitro blue tetrazolium nals. Therefore, AML is a disorder of impaired hematopoietic OBAT obatoclax cell differentiation and apoptosis. Therapies aimed at resum- ing the process of maturation and apoptosis in leukemic cells are currently the most promising anti-AML strategies [1]. * Małgorzata Opydo-Chanek [email protected] Treatment of acute promyelocytic leukemia (APL), a subtype of AML, with all-trans-retinoic acid (ATRA) was the first model of differentiation-targeted therapy [2]. Despite its spec- 1 Department of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, tacular clinical success, ATRA-based therapy has limitations 30-387 Kraków, Poland due to both the induction of potentially life-threatening toxic- 2 Department of Physiology and Toxicology of Reproduction, Institute ity and the acquisition of resistance in some patients [3]. of Zoology and Biomedical Research, Jagiellonian University, Moreover, most non-APL AML patients do not benefit from Gronostajowa 9, 30-387 Kraków, Poland ATRA therapy. Therefore, the search for new compounds that Invest New Drugs can efficiently and selectively induce differentiation and apo- consequently leads to apoptosis in cancer cells [19, 20]. ptosis in leukemic cells remains essential for the future of Moreover, obatoclax enhances apoptosis when combined with AML therapy, especially concerning non-APL subtypes of conventional chemotherapeutics or targeted therapy drugs, as AML. has been shown in preclinical in vitro and in vivo studies [21, Recently, proteins of the B cell lymphoma-2 (Bcl-2) family 22]. Several phase I and II clinical trials have been completed have attracted considerable interest as therapeutic targets in investigating the use of obatoclax as a single agent in the AML [4–6]. The Bcl-2 protein family is a key regulator of treatment of solid tumors and hematological malignancies, the mitochondrial pathway of apoptosis. Based on structural including AML, chronic lymphocytic leukemia, acute lym- and functional features, three different subclasses of the Bcl-2 phoblastic leukemia, myelodysplastic syndrome and protein family are distinguished. Proteins of the anti-apoptotic Hodgkin’s lymphoma, however, all of these trials demonstrat- Bcl-2 subfamily, such as Bcl-2, Bcl-xL and Mcl-1, inhibit ed only modest efficacy [23]. Additionally, evidence from apoptosis by preserving mitochondrial membrane integrity clinical trials has indicated that obatoclax may be more effec- [7]. These proteins bind to and inactivate Bax and Bak, the tive when used in combination with other anti-cancer thera- multidomain members of the pro-apoptotic subfamily. In re- peutics, however further studies are required to fully investi- sponse to apoptotic signals, Bax and/or Bak undergo confor- gate this issue [23, 24]. Despite the clinical developments mational changes and oligomerize, forming pores in the outer regarding obatoclax, its anti-cancer activity is still not fully mitochondrial membrane. Mitochondrial membrane perme- understood. Recent investigations have highlighted additional abilization leads to the release of death-promoting proteins mechanisms behind obatoclax’s anti-cancer actions, including and, consequently, activation of the initiator caspase 9 and the inhibition of proliferation and migration of colorectal [25] effector caspases 3 and 7, resulting in the morphological and and esophageal [26] cancer cells. Initial studies have shown biochemical changes associated with apoptosis [8]. Proteins of that obatoclax is capable of exerting anti-AML effects through the third subfamily, named “BH3-only” proteins, carry out the induction of cell cycle arrest and inhibition of leukemic their pro-apoptotic function through two mechanisms: neutral- cell growth [19, 27, 28]. Further elucidation of obatoclax’s ization of the anti-apoptotic Bcl-2 subfamily proteins and di- mechanism of action may provide important data in regard rect activation of the pro-apoptotic effectors Bax and Bak [7, to improving its therapeutic applications. 8]. The balance between anti-apoptotic and pro-apoptotic To our knowledge, thus far, the pro-differentiating effect of members of the Bcl-2 family, mediated through protein- obatoclax on AML cells has not been investigated. Therefore, protein interactions, determines cell survival or death. the present study was designed to determine the anti-AML Besides being important regulators of apoptosis, proteins efficacy of obatoclax by examining its influence on differen- of the Bcl-2 family also govern other cellular pathways, in- tiation and apoptosis in human AML HL-60 cells. The HL-60 cluding the cell cycle, proliferation and differentiation [9, 10]. cell line has been widely applied in studies on hematopoietic Several studies have shown that Bcl-2 proteins are expressed cell proliferation, differentiation and death [29, 30]. This cell in early hematopoietic progenitors and regulated during the line was derived from a 36-year-old woman who was initially differentiation of myeloid cells [11]. Moreover, there is considered to have APL, although subsequent evaluation has mounting evidence that the balanced regulation of Bcl-2 pro- indicated that the leukemia from which HL-60 cells were de- teins is crucially important in the generation, maintenance and rived is more appropriately classified as AML with maturation function of the hematopoietic system [12–14]. Importantly, [29]. HL-60 cell cultures comprise maturation-arrested cells the expression of Bcl-2 and/or other members of the anti- with properties similar to those of myeloblasts and apoptotic subfamily is often elevated in hematological malig- promyelocytes, such as their characteristic large, rounded nu- nancies, either as a result of gene translocations or amplifica- clei containing two to four distinct nucleoli, fine chromatin tions, or due to mechanisms independent from genomic aber- and a basophilic cytoplasm with azurophilic granules [29]. rations [15]. The over-expression of anti-apoptotic Bcl-2 fam- These cells can be induced to differentiate in vitro into cells ily members contributes to enhanced leukemic cell survival, of diverse myeloid lineages, depending on which reagents are chemoresistance and poor clinical outcomes, suggesting that used. Agents such as ATRA and dimethyl sulfoxide have been these proteins may be an attractive therapeutic target [16–18]. reported to induce granulocytic differentiation of HL-60 cells, Obatoclax, a synthetic indole bipyrrole derivative of bacte- whereas 12-O-tetradecanoylphorbol-13-acetate and vitamin rial prodiginines, is a small-molecule inhibitor of the anti- D3 have been shown to induce their differentiation into apoptotic proteins of the Bcl-2 family that was designed to monocytes/macrophages [30]. The course of HL-60 cell dif- mimic pro-apoptotic BH3-only proteins in binding to anti- ferentiation is accompanied by a number of changes in these apoptotic Bcl-2 family members. Obatoclax antagonizes cells that can be monitored through morphological, histo- Bcl-2, Bcl-xL, Bcl-w and Mcl-1, thus leading to the activation chemical
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