TY - JOUR
T1 - A novel dual HDAC and HSP90 inhibitor, MPT0G449, downregulates oncogenic pathways in human acute leukemia in vitro and in vivo
AU - Wu, Yi Wen
AU - Chao, Min Wu
AU - Tu, Huang Ju
AU - Chen, Liang Chieh
AU - Hsu, Kai Cheng
AU - Liou, Jing Ping
AU - Yang, Chia Ron
AU - Yen, Shih Chung
AU - HuangFu, Wei Chun
AU - Pan, Shiow Lin
N1 - Funding Information:
Y.W.W. designed the research and performed the majority of the experiments. M.W.C. and H.J.T. provided technical and material support. L.C.C., K.C.H., and S.C. Y. were responsible for molecular docking analysis. J.P.L. provided the dual effect compound, MPT0G449. S.L.P. designed the animal study. M.W.C., C.R.Y., W.H.V., W.C.H.F., and S.L.P. organized the manuscript. All authors approved the final manuscript. This work was financially supported by the Ministry of Science and Technology, Taiwan (grant no. MOST 107-2320-B-038-044-MY3) and the TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (grant no. DP2-109-21121-03-C-07-05). This research was partially supported by the Warshel Institute for Computational Biology City and Longgang District in the People’s Republic of China.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/5
Y1 - 2021/5
N2 - Acute leukemia is a highly heterogeneous disease; therefore, combination therapy is commonly used for patient treatment. Drug–drug interaction is a major concern of combined therapy; hence, dual/multi-target inhibitors have become a dominant approach for cancer drug development. HDACs and HSP90 are involved in the activation of various oncogenic signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAF/MEK/ERK, which are also highly enriched in acute leukemia gene expression profiles. Therefore, we suggest that dual HDAC and HSP90 inhibitors could represent a novel therapeutic approach for acute leukemia. MPT0G449 is a dual effect inhibitor, and it showed cytotoxic effectiveness in acute leukemia cells. Molecular docking analysis indicated that MPT0G449 possessed dual HDAC and HSP90 inhibitory abilities. Furthermore, MPT0G449 induced G2 arrest and caspase-mediated cell apoptosis in acute leukemia cells. The oncogenic signaling molecules AKT, mTOR, STAT3, STAT5, MEK, and ERK were significantly downregulated after MPT0G449 treatment in HL-60 and MOLT-4 cells. In vivo xenograft models confirmed the antitumor activity and showed the upregulation of acetyl-histone H3 and HSP70, biomarkers of pan-HDAC and HSP90 inhibition, with MPT0G449 treatment. These findings suggest that the dual inhibition of HDAC and HSP90 can suppress the expression of oncogenic pathways in acute leukemia, and MPT0G449 represents a novel therapeutic for anticancer treatment.
AB - Acute leukemia is a highly heterogeneous disease; therefore, combination therapy is commonly used for patient treatment. Drug–drug interaction is a major concern of combined therapy; hence, dual/multi-target inhibitors have become a dominant approach for cancer drug development. HDACs and HSP90 are involved in the activation of various oncogenic signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAF/MEK/ERK, which are also highly enriched in acute leukemia gene expression profiles. Therefore, we suggest that dual HDAC and HSP90 inhibitors could represent a novel therapeutic approach for acute leukemia. MPT0G449 is a dual effect inhibitor, and it showed cytotoxic effectiveness in acute leukemia cells. Molecular docking analysis indicated that MPT0G449 possessed dual HDAC and HSP90 inhibitory abilities. Furthermore, MPT0G449 induced G2 arrest and caspase-mediated cell apoptosis in acute leukemia cells. The oncogenic signaling molecules AKT, mTOR, STAT3, STAT5, MEK, and ERK were significantly downregulated after MPT0G449 treatment in HL-60 and MOLT-4 cells. In vivo xenograft models confirmed the antitumor activity and showed the upregulation of acetyl-histone H3 and HSP70, biomarkers of pan-HDAC and HSP90 inhibition, with MPT0G449 treatment. These findings suggest that the dual inhibition of HDAC and HSP90 can suppress the expression of oncogenic pathways in acute leukemia, and MPT0G449 represents a novel therapeutic for anticancer treatment.
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U2 - 10.1038/s41389-021-00331-0
DO - 10.1038/s41389-021-00331-0
M3 - Article
AN - SCOPUS:85105782694
SN - 2157-9024
VL - 10
JO - Oncogenesis
JF - Oncogenesis
IS - 5
M1 - 39
ER -