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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01276

Chidamide Enhances the Cytotoxicity of Cytarabine and Sorafenib in Acute Myeloid Leukemia Cells by Modulating H3K9me3 and Autophagy Levels

 Huang he1, Yang wenbing1, Dong aishu2, Yao rongxing1 and  Guo Wenjian1*
  • 1Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, China
  • 2Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, China

Previous studies showed that Chidamide enhances the cytotoxicity of drugs in acute myeloid leukemia (AML) cells. Therefore, we examined whether Chidamide enhanced the cytotoxicity of drugs in AML cells by affecting H3K9me3 and autophagy levels. AML cells (THP-1 and MV4-11 cells) were treated with Chidamide, Cytarabine (Ara-c), or Sorafenib alone or in combination. Cell proliferation and survival rates were analyzed by MTT, flow cytometry, and western blotting assays. The results showed that a low dose of Chidamide enhanced the cytotoxicity of Ara-c or Sorafenib in AML cells, decreasing proliferation and increasing apoptosis. H3K9me3 levels as assessed by western blotting were upregulated by Chidamide treatment. ChIP-seq, which was used to investigate potential signaling pathways, indicated that the autophagy pathway might play a role in the effects of Chidamide. The level of autophagy induced in AML cells upon treatment with Ara-c or Sorafenib was inhibited by Chidamide, and autophagy markers (LC3, P62) were tested by western blotting. SIRT1 mRNA and protein levels were lower in AML cells treated with Ara-c or Sorafenib in combination with Chidamide than in cells treated with these drugs alone. Additionally, the Integrative Genomics Viewer results indicate that the H3K9me3 changes were related to SIRT1-binding sites. Together, these results show that Chidamide enhances the cytotoxicity of two chemotherapy drugs in AML cells by increasing the H3K9me3 level and inhibiting autophagy via decreasing the expression of SIRT1. Chidamide may be a potential treatment strategy for AML in the future, especially for refractory AML patients.

Keywords: Acute Myeloid Leukemia, Chidamide, H3K9me3, Autophagy, ‎ SIRT1‎

Received: 11 Mar 2019; Accepted: 04 Nov 2019.

Copyright: © 2019 he, wenbing, aishu, rongxing and Wenjian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Guo Wenjian, Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China, pxzc1981@163.com