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Reversine, a Novel Aurora Kinases Inhibitor, Inhibits Colony Formation of Human Acute Myeloid Leukemia Cells

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Reversine, a Novel Aurora Kinases Inhibitor, Inhibits Colony Formation of Human Acute Myeloid Leukemia Cells 1140 Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells Anna Morena D’Alise,1 Giovanni Amabile,1 More recently, Anastasia et al. showed that reversine can Mariangela Iovino,1 Francesco Paolo Di Giorgio,1 facilitate the differentiation of human fibroblasts into Marta Bartiromo,1 Fabio Sessa,2 Fabrizio Villa,2 skeletal muscle cells in vitro and in vivo (2). Thus, reversine Andrea Musacchio,2 and Riccardo Cortese1 has the ability to reprogram somatic cells to a state of increased plasticity that can be manipulated to direct 1CEINGE, Biotecnologie Avanzate, Naples, Italy and differentiation in different cell types. 2 Department of Experimental Oncology, European Institute of The identification of conditions that set the stage for cell Oncology, Milan, Italy differentiation is also relevant to cancer therapy, where the ability to force the differentiation of cancer cells is expected Abstract to counteract their proliferation potential. At the beginning The demonstration that the small synthetic molecule of our studies, we asked if pretreatment with reversine reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine] could promote the differentiation of cancer cells. As shown promotes the dedifferentiation of committed cells into below, our results are consistent with the hypothesis that multipotent progenitor-type cells has raised hopes on the reversine is a facilitator of tumor cell differentiation. For exploitation of this small chemical tool for the generation instance, reversine induces the expression of reelin, a of stem cells. Here, we show that reversine causes a neuronal marker selectively expressed in GABAergic failure in cytokinesis and induces polyploidization. These neurons (3) in the human embryonal carcinoma cell line effects of reversine are due to the inhibition of Aurora A N TERA-2 (NT2). Reversine also induces the expression of and B, two related kinases that are implicated in several CD11b, a gene marker of cell differentiation, in the HL60 aspects of mitosis and that are frequently amplified and leukemic cell line. overexpressed in human tumors. Reversine inhibits the In an attempt to provide a molecular explanation for the phosphorylation of histone H3, a direct downstream target function of reversine, we tested its activity on a broad panel of Aurora kinases. Similarly to the Aurora kinase inhibitor of protein kinases and found that reversine specifically VX-680, which has recently entered phase II clinical trials inhibits the function of Aurora kinases both in vitro and for cancer treatment, reversine inhibited colony formation in cell-based assays. Aurora kinases are serine/threonine of leukemic cells from patients with acute myeloid kinases that play a prominent role in mitotic regulation leukemia but was significantly less toxic than VX-680 on (4, 5). The Aurora A kinase, the ‘‘polar’’ kinase, resides at cells from healthy donors. The crystal structure of the spindle poles during mitosis and is implicated in the reversine-Aurora B kinase complex shows that reversine is control of centrosome duplication, maturation, and sepa- a novel class of ATP-competitive Aurora kinase inhibitors. ration (6). Aurora A is also important for the formation of a Thus, although our studies raise serious doubts on the bipolar mitotic spindle. Aurora B, the ‘‘equatorial’’ kinase, application of reversine in regenerative medicine, they is part of a chromosome passenger complex that controls support the paradigm that reversine might be a useful the organization of the centromere-kinetochore region agent in cancer chemotherapy. [Mol Cancer Ther and is directly implicated in the control of microtubule- 2008;7(5):1140–9] kinetochore attachment, in which it plays an essential function by correcting faulty microtubule-kinetochore attachments. Later in the cell cycle, Aurora B plays a Introduction prominent role in cytokinesis (7). Much less is known about Reversine, a substituted purine analogue, was originally the physiologic role of the Aurora kinase C: it appears that shown to promote the dedifferentiation of myotubes it is a chromosomal passenger protein, like Aurora kinase derived from the murine myoblast cell line C2C12 (1). B, whose function it can complement (8). Aurora kinases have also emerged as valuable targets in cancer therapy, not least because they appear to be Received 9/7/07; revised 2/4/08; accepted 2/17/08. frequently overexpressed in human tumors (7). Several The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked small-molecule inhibitors of Aurora kinases, initially advertisement in accordance with 18 U.S.C. Section 1734 solely to generated in the pharmaceutical industry, have leaked into indicate this fact. general laboratory use. In addition to classic studies of Note: A.M. D’Alise and G. Amabile have contributed equally to this work. genetic inactivation in different cell types and organisms, Requests for reprints: Riccardo Cortese, CEINGE, Biotecnologie the small-molecule compounds targeting Aurora kinases Avanzate, Via Comunale Margherita 482, 80131 Naples, Italy. Phone: 39-335-81-04-832; Fax: 39-6-978-49-266. in living cells have helped dissecting the specific cellular E-mail: [email protected] functions of the Aurora A and B family members. Copyright C 2008 American Association for Cancer Research. Most notably, the effects on cell division of Hesperadin doi:10.1158/1535-7163.MCT-07-2051 (Boehringer Ingelheim) and ZM447439 and related compounds MolCancerTher2008;7(5).May2008 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2008 American Association for Cancer Research. Molecular Cancer Therapeutics 1141 (AstraZeneca) have been described in detail (9–11). Dickinson) for 30 min at room temperature. After incuba- Collectively, these studies have provided a blueprint tion, the cells were washed twice with diluent solution against which the function of other potential Aurora (PBS containing 1% bovine serum albumin and 0.1% inhibitors can be tested. Here, we show that reversine NaN3), fixed with 2% paraformaldehyde, and analyzed seems to inhibit preferentially the Aurora B kinase in a cell on a FACSCalibur flow cytometer (Becton Dickinson). The culture system, as it provides effects that are similar to fluorescence intensity of the viable cells (identified by their those previous attributed to this kinase, including the light scattering characteristics) was analyzed using Cell- inhibition of cytokinesis and the induction of polyploidy. Quest software and represented as percentage of CD11b+ We tested the antitumor effects of reversine on primary cells. blood tumors and found that reversine has strong To measure cell death, we did Annexin V analysis on antitumor activity associated with good tolerability by HCT116 tumor cell line. The cells were treated with the normal cells. Finally, the determination of the crystal drug for 0 and 24 h then were washed with ice-cold PBS structure of the reversine-Aurora B complex reveals that and incubated in a binding buffer [125 mmol/L NaCl, reversine defines a novel class of Aurora kinase active site 25 mmol/L HEPES (pH 7.5), 1% bovine serum albumin] inhibitors. with Annexin V/propidium iodide (1 Ag/0.2 Ag/mL) in a 100 AL volume for 30 min in darkon ice; 0.5 mL binding buffer was added and cells were analyzed by flow Materials and Methods cytometry using a Becton Dickinson FACS CANTO. Cell Culture and Treatment Cell Cycle Analysis HeLa cervical carcinoma cells, T47D breast cancer cells, HCT116 and HL60 cells were incubated with either and NT2 cells (all from American Type Culture Collection) 5 Amol/L reversine or DMSO 0.01%. Cells were harvested were cultured in growth medium consisting of high- and fixed in 70% ethanol overnight. After double washing glucose DMEM supplemented with 2 mmol/L glutamine, with PBS, cells were labeled with cell cycle staining reagent 100 IU/mL penicillin, 100 Ag/mL streptomycin (Invitrogen), PBS, 0.1% Triton X-100, 200 Ag/mL DNase-free RNase, and and 10% (v/v) fetal bovine serum (FBS; HyClone). The 25 Ag/mL propidium iodide (Invitrogen) and incubated human colon cancer cell line HCT116 (American Type at room temperature in the darkfor 30 min. DNA content Culture Collection) was maintained in McCoy’s 5A modi- was analyzed using FACSCalibur (Becton Dickinson). fied medium supplemented with 10% FBS, 100 units/mL Immunofluorescence penicillin, and 100 Ag/mL streptomycin. A375 melanoma HCT116 cells (5 Â 104) were cultured on poly-lysine cells were grown in DMEM supplemented with 2 mmol/L (Sigma)–coated coverslips. For analysis of histone H3 glutamine, 100 IU/mL penicillin, 100 Ag/mL streptomycin phosphorylation, cells were fixed in 4% paraformaldehyde (Invitrogen), and 15% (v/v) FBS (HyClone). Promyelocytic for 10 min at room temperature and then permeabilized leukemia cells HL60 were grown in RPMI with 2 mmol/L with PBS/0.1% Triton X-100 for 5 min at room temperature. glutamine, 100 IU/mL penicillin, 100 Ag/mL streptomycin Cells were incubated with the primary antibody anti- (Invitrogen), and 10% (v/v) FBS (HyClone), whereas Ser10P-H3 (5-10 Ag/mL; Upstate) followed by a FITC MCF-7 breast cancer cells were grown in MEM supple- conjugate antibody to rabbit IgG (1:3,000; Sigma) and then mented with 2 mmol/L glutamine, 100 IU/mL penicillin, counterstained with 0.5 Ag/mL 4¶,6-diamidino-2-phenyl- 100 Ag/mL streptomycin, 1% nonessential amino acids indole. (Invitrogen), and 10% (v/v) FBS (HyClone).
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