title: YM155 induces apoptosis in p53-deficient T-acute lymphoblastic leukemia cells independent of survivin inhibition.
abstract: T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from the malignant transformation of T-cell progenitors. Despite the significant progress in current treatment, challenges remain the lifelong morbidity after current chemotherapy regimens and postrelapse survival. In addition, patients with T-ALL have inferior outcomes compared with those with B-cell precursor; consequently, novel therapeutic approaches are still necessary to improve the outcome in this cohort. YM155 is an imidazolium derivative originally discovered as a suppressant of survivin expression. It has been reported that YM155 has potent antiproliferative activity on a variety of human cancer cell lines; however, its effects in T-ALL cells have been underexplored. The aim of the present study was to examine the effects of YM155 on p53-deficient T-ALL cell lines, JURKAT and CCRF-CEM. Resazurin dye was used to evaluate cell viability. Colony formation was observed in MethoCult methylcellulose medium. Apoptotic cells were detected by flow cytometry (annexin V labeling and TUNEL assay). Cell cycle analysis was carried out by DNA quantification in flow cytometry. DNA damage was assessed using a comet assay and the survivin expression profile was evaluated by real-time PCR and immunoblotting. YM155 treatment decreased cell viability and clonogenicity capacity of T-ALL cells, increased the apoptosis index and DNA damage, and altered the cell cycle dynamic, independent of survivin inhibition. Taken together, the data reinforce that YM155 may be useful as a therapeutic possibility to combat leukemia.
authors.affiliation: aInstitute of Natural Science bDepartment of Cell and Developmental Biology, Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil.
authors.forename: Leilane
authors.initials: L
authors.lastname: Sales
authors.forename: Graziella R
authors.initials: GR
authors.lastname: de Sousa
authors.forename: Guilherme Á
authors.initials: GÁ
authors.lastname: Ferreira-Silva
authors.forename: Angel M
authors.initials: AM
authors.lastname: Castro-Gamero
authors.forename: Marisa
authors.initials: M
authors.lastname: Ionta
authors.forename: Jaqueline C
authors.initials: JC
authors.lastname: de Oliveira
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D002675:Child, Preschool; D004249:DNA Damage; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D019169:Jurkat Cells; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C523798:sepantronium