A novel dual HDAC and HSP90 inhibitor, MPT0G449, downregulates oncogenic pathways in human acute leukemia in vitro and in vivo

Yi-Wen Wu,Jing-Ping Liou,Shih-Chung Yen,Shiow-Lin Pan,Kai-Cheng Hsu,Chia-Ron Yang,Min-Wu Chao,Wei-Chun Huangfu,Huang-Ju Tu,Liang-Chieh Chen

doi:10.1038/s41389-021-00331-0

Abstract

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.

Highlights

Acute leukemia is a type of hematologic malignancy caused by the rapid proliferation of abnormal immature blood cells
We have synthesized a series of dual Histone deacetylases (HDACs) and Heat shock protein 90 (HSP90) inhibitors to examine their anticancer efficacy[30]
Since HDACs and HSP90 are both involved in the critical roles in leukemogenesis, we evaluated the cytotoxic effectiveness of dual HDAC/HSP90 inhibitors

Summary

Introduction

Acute leukemia is a type of hematologic malignancy caused by the rapid proliferation of abnormal immature blood cells. Unpredictable drug–drug interactions, and the dynamic pharmacokinetic and pharmacological issues of combination treatment with two (or more) anticancer agents might lead to unexpected side effects or lower treatment efficacies[2,3]. There are four pan-HDAC inhibitors, vorinostat, romidepsin, belinostat, and panobinostat, approved by the US Food and Drug Administration (FDA) for leukemia and other hematological malignancies[7,8,9,10]. These inhibitors exhibit successful anticancer activity by inducing growth inhibition, cell cycle arrest, and apoptosis[11]. We attempted to identify a compound that can target both HDACs and other oncogenic proteins to produce an optimum antitumor effect and decrease unwanted reactions

Methods

Results

Conclusion