Unknown

Dataset Information

0

Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo.


ABSTRACT: MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.

SUBMITTER: Qi W 

PROVIDER: S-EPMC4847803 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

2015-01-01 | S-EPMC4282784 | BioStudies
1000-01-01 | S-EPMC4237862 | BioStudies
2012-01-01 | S-EPMC3517755 | BioStudies
2013-01-01 | S-EPMC3823972 | BioStudies
2011-01-01 | S-EPMC3167033 | BioStudies
2015-01-01 | S-EPMC4401631 | BioStudies
2015-01-01 | S-EPMC4413661 | BioStudies
2014-01-01 | S-EPMC4199830 | BioStudies
2014-01-01 | S-EPMC4279392 | BioStudies
2013-01-01 | S-EPMC3548976 | BioStudies