TY - JOUR
T1 - Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo
AU - Qi, Wenxiu
AU - Zhang, Wenbo
AU - Edwards, Holly
AU - Chu, Roland
AU - Madlambayan, Gerard J.
AU - Taub, Jeffrey W.
AU - Wang, Zhihong
AU - Wang, Yue
AU - Li, Chunhuai
AU - Lin, Hai
AU - Ge, Yubin
N1 - Funding Information:
This study was supported by a Start-up Fund from Jilin University, Changchun, China, and grants from the National Natural Science Foundation of China, NSFC 31271477 and NSFC 31471295, and the Natural Science Fund, Department of Science and Technology, Jilin Province, China. The funders had no role in study design, data collection, analysis and interpretation of data, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2015 Taylor & Francis Group, LLC.
PY - 2015/12/2
Y1 - 2015/12/2
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - CHK1
KW - MK-1775
KW - Panobinostat
KW - Wee1
UR - http://www.scopus.com/inward/record.url?scp=84954479069&partnerID=8YFLogxK
U2 - 10.1080/15384047.2015.1095406
DO - 10.1080/15384047.2015.1095406
M3 - Article
C2 - 26529495
AN - SCOPUS:84954479069
SN - 1538-4047
VL - 16
SP - 1784
EP - 1793
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 12
ER -