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

Smith, Amanda M., Little, Erica B., Zivanovic, Andjelija, Hong, Priscilla, Liu, Alfred K. S., Burow, Rachel, Stinson, Caedyn, Hallahan, Andrew R. and Moore, Andrew S. (2015) Targeting Survivin with YM155 (Sepantronium Bromide): A novel therapeutic strategy for paediatric acute myeloid leukaemia. Leukemia Research, 39 4: 435-444. doi:10.1016/j.leukres.2015.01.005

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Author Smith, Amanda M.
Little, Erica B.
Zivanovic, Andjelija
Hong, Priscilla
Liu, Alfred K. S.
Burow, Rachel
Stinson, Caedyn
Hallahan, Andrew R.
Moore, Andrew S.
Title Targeting Survivin with YM155 (Sepantronium Bromide): A novel therapeutic strategy for paediatric acute myeloid leukaemia
Journal name Leukemia Research   Check publisher's open access policy
ISSN 1873-5835
0145-2126
Publication date 2015-04-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.leukres.2015.01.005
Open Access Status File (Author Post-print)
Volume 39
Issue 4
Start page 435
End page 444
Total pages 10
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon Press
Language eng
Formatted abstract
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 0.038 μM. 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.
Keyword AML
Paediatric
Survivin
YM155
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID APP1036907
CT13507
WS1839566
Institutional Status UQ

 
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