Targeting Survivin with YM155 (Sepantronium Bromide): A novel therapeutic strategy for paediatric acute myeloid leukaemia

• Published in: Leukemia research Vol. 39; no. 4; pp. 435 - 444
• Main Authors: Smith, Amanda M., Little, Erica B., Zivanovic, Andjelija, Hong, Priscilla, Liu, Alfred K.S., Burow, Rachel, Stinson, Caedyn, Hallahan, Andrew R., Moore, Andrew S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2015
• Subjects: AML; Apoptosis - drug effects; Blotting, Western; Cell Cycle - drug effects; Cell Proliferation - drug effects; Child; Flow Cytometry; Hematology, Oncology and Palliative Medicine; Humans; Imidazoles - pharmacology; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Naphthoquinones - pharmacology; Paediatric; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Survivin; Tumor Cells, Cultured; YM155; AML; Paediatric; Survivin; YM155
• ISSN: 0145-2126; 1873-5835; 1873-5835
• DOI: 10.1016/j.leukres.2015.01.005

•YM155 inhibits proliferation and induces apoptosis of AML in vitro.•Survivin mRNA and protein expression is downregulated in AML cells treated with YM155.•YM155 treatment induced a DNA damage response in 2 of 6 paediatric AML cell lines.•YM155 induces apoptosis in diagnostic bone marrow samples from children with AML. Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The Survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038μM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of Survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of Survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation.