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Sensitization of chemo-resistant human chronic myeloid leukemia stem-like cells to Hsp90 inhibitor by SIRT1 inhibition.

Kim HB, Lee SH, Um JH, Kim MJ, Hyun SK, Gong EJ, Oh WK, Kang CD, Kim SH - Int. J. Biol. Sci. (2015)

Bottom Line: 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, β-catenin, c-Myc, mutant p53 (mut p53), BCRP and P-glycoprotein (P-gp) as well as CD44.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.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.

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, β-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.

No MeSH data available.


Related in: MedlinePlus

Potentiation of cytotoxicity of Hsp90 inhibitor in CD44high K562 cells by SIRT1 inhibitors. Cells were treated with serial doses of 17-AAG (A) or AUY922 (B) in the presence or absence of amurensin G (0.1- and 10 μg/ml) or EX527 (10- and 50 nM). Percentage of cell survival was determined after 96 h of incubation using MTT assay. * p < 0.05, **p < 0.01 and ***p < 0.001.
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Figure 7: Potentiation of cytotoxicity of Hsp90 inhibitor in CD44high K562 cells by SIRT1 inhibitors. Cells were treated with serial doses of 17-AAG (A) or AUY922 (B) in the presence or absence of amurensin G (0.1- and 10 μg/ml) or EX527 (10- and 50 nM). Percentage of cell survival was determined after 96 h of incubation using MTT assay. * p < 0.05, **p < 0.01 and ***p < 0.001.

Mentions: Since SIRT1 inhibition resulted in suppression of the up-regulated CSC-related molecules in CD44high K562 cells, it was determined if SIRT1 inhibition could reverse the resistance of CD44high K562 cells to Hsp90 inhibitors. When CD44high K562 cells were treated with Hsp90 inhibitor (17-AAG or AUY922) after SIRT1 knock-down, the sensitivity of the cells to 17-AAG or AUY922 was significantly enhanced in comparison with treatment with 17-AAG or AUY922 alone (Fig. 6A and B). To further examine the potential relationship between SIRT1 activity and sensitivity to Hsp90 inhibitor in CD44high K562 cells, we tested the combination effect of Hsp90 inhibitors with SIRT1 inhibitors in the cells. When CD44high K562 cells were co-treated with 17-AAG and amurensin G or EX527, a known chemical inhibitor of SIRT1 37, there was a significant dose-dependent potentiation of 17-AAG-induced cytotoxicity against CD44high K562 cells by amurensin G or EX527 (Fig. 7A). Similarly, the combination effect of AUY922 and SIRT1 inhibitor (amurensin G or EX527) was observed in CD44high K562 cells (Fig. 7B). These results demonstrated that the susceptibility of CD44high K562 cells to Hsp90 inhibitors can be significantly enhanced by SIRT1 inhibitors.


Sensitization of chemo-resistant human chronic myeloid leukemia stem-like cells to Hsp90 inhibitor by SIRT1 inhibition.

Kim HB, Lee SH, Um JH, Kim MJ, Hyun SK, Gong EJ, Oh WK, Kang CD, Kim SH - Int. J. Biol. Sci. (2015)

Potentiation of cytotoxicity of Hsp90 inhibitor in CD44high K562 cells by SIRT1 inhibitors. Cells were treated with serial doses of 17-AAG (A) or AUY922 (B) in the presence or absence of amurensin G (0.1- and 10 μg/ml) or EX527 (10- and 50 nM). Percentage of cell survival was determined after 96 h of incubation using MTT assay. * p < 0.05, **p < 0.01 and ***p < 0.001.
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Related In: Results  -  Collection

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Figure 7: Potentiation of cytotoxicity of Hsp90 inhibitor in CD44high K562 cells by SIRT1 inhibitors. Cells were treated with serial doses of 17-AAG (A) or AUY922 (B) in the presence or absence of amurensin G (0.1- and 10 μg/ml) or EX527 (10- and 50 nM). Percentage of cell survival was determined after 96 h of incubation using MTT assay. * p < 0.05, **p < 0.01 and ***p < 0.001.
Mentions: Since SIRT1 inhibition resulted in suppression of the up-regulated CSC-related molecules in CD44high K562 cells, it was determined if SIRT1 inhibition could reverse the resistance of CD44high K562 cells to Hsp90 inhibitors. When CD44high K562 cells were treated with Hsp90 inhibitor (17-AAG or AUY922) after SIRT1 knock-down, the sensitivity of the cells to 17-AAG or AUY922 was significantly enhanced in comparison with treatment with 17-AAG or AUY922 alone (Fig. 6A and B). To further examine the potential relationship between SIRT1 activity and sensitivity to Hsp90 inhibitor in CD44high K562 cells, we tested the combination effect of Hsp90 inhibitors with SIRT1 inhibitors in the cells. When CD44high K562 cells were co-treated with 17-AAG and amurensin G or EX527, a known chemical inhibitor of SIRT1 37, there was a significant dose-dependent potentiation of 17-AAG-induced cytotoxicity against CD44high K562 cells by amurensin G or EX527 (Fig. 7A). Similarly, the combination effect of AUY922 and SIRT1 inhibitor (amurensin G or EX527) was observed in CD44high K562 cells (Fig. 7B). These results demonstrated that the susceptibility of CD44high K562 cells to Hsp90 inhibitors can be significantly enhanced by SIRT1 inhibitors.

Bottom Line: 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, β-catenin, c-Myc, mutant p53 (mut p53), BCRP and P-glycoprotein (P-gp) as well as CD44.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.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.

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, β-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.

No MeSH data available.


Related in: MedlinePlus