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Publication
Sensitization of Chemo-Resistant Human Chronic Myeloid Leukemia Stem-Like Cells
to Hsp90 Inhibitor by SIRT1 Inhibition.
Authors Kim HB, Lee SH, Um JH, Kim MJ, Hyun SK, Gong EJ, Oh WK, Kang CD, Kim SH
Submitted By Submitted Externally on 7/24/2015
Status Published
Journal International journal of biological sciences
Year 2015
Date Published
Volume : Pages 11 : 923 - 934
PubMed Reference 26157347
Abstract Development of effective therapeutic strategies to eliminate cancer stem-like
cells (CSCs), which play a major role in drug resistance and disease recurrence,
is critical to improve cancer treatment outcomes. The current investigation was
undertaken to examine the effectiveness of the combination treatment of Hsp90
inhibitor and SIRT1 inhibitor in inhibiting the growth of chemo-resistant
stem-like cells isolated from human chronic myeloid leukemia K562 cells.
Inhibition of SIRT1 by use of SIRT1 siRNA or SIRT1 inhibitors (amurensin G and
EX527) effectively potentiated sensitivity of Hsp90 inhibitors (17-AAG and
AUY922) in CD44(high) K562 stem-like cells expressing high levels of CSC-related
molecules including Oct4, CD34, ß-catenin, c-Myc, mutant p53 (mut p53), BCRP and
P-glycoprotein (P-gp) as well as CD44. SIRT1 depletion caused significant
down-regulation of heat shock factor 1 (HSF1)/heat shock proteins (Hsps) as well
as these CSC-related molecules, which led to the sensitization of CD44(high)
K562 cells to Hsp90 inhibitor by SIRT1 inhibitor. Moreover, 17-AAG-mediated
activation of HSF1/Hsps and P-gp-mediated efflux, major causes of Hsp90
inhibitor resistance, was suppressed by SIRT1 inhibitor in K562-CD44(high)
cells. Our data suggest that combined treatment with Hsp90 inhibitor and SIRT1
inhibitor could be an effective therapeutic approach to target CSCs that are
resistant to current therapies.




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