Chidamide increases the sensitivity of refractory or relapsed acute myeloid leukemia cells to anthracyclines via regulation of the HDAC3 -AKT-P21-CDK2 signaling pathway

• Published in: Journal of experimental & clinical cancer research Vol. 39; no. 1; pp. 278 - 19
• Main Authors: Wang, Hao, Liu, Yu-chen, Zhu, Cheng-ying, Yan, Fei, Wang, Meng-zhen, Chen, Xiao-su, Wang, Xiao-kai, Pang, Bao-xu, Li, Yong-hui, Liu, Dai-hong, Gao, Chun-ji, Liu, Shu-jun, Dou, Li-ping
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.12.2020; BioMed Central; BMC
• Subjects: Adolescent; Adult; Aged; Aminopyridines - administration & dosage; Animals; Anthracyclines; Anthracyclines - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Benzamides - administration & dosage; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Bone marrow; Cancer; Cancer therapies; Cell Cycle; Cell growth; Cell Proliferation; Chemotherapy; Chidamide; Child; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Diseases; Drug resistance; Drug Resistance, Neoplasm; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genomes; HDAC3; Hematology; Histone deacetylase; Histone deacetylase inhibitors; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Induction therapy; Informed consent; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Medical prognosis; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neutrophils; Penicillin; PI3K-AKT signaling pathways; Plasmids; Prognosis; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Reagents; Refractory or relapsed acute myeloid leukemia; Relapse; Salvage Therapy; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Young Adult; United States > US; PI3K-AKT signaling pathways; Refractory or relapsed acute myeloid leukemia; Histone deacetylase; HDAC3; Histone deacetylase inhibitors; Chidamide
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-020-01792-8

Induction therapy for acute myeloid leukemia (AML) is an anthracycline-based chemotherapy regimen. However, many patients experience a relapse or exhibit refractory disease (R/R). There is an urgent need for more effective regimens to reverse anthracycline resistance in these patients. In this paper, Twenty-seven R/R AML patients with anthracycline resistance consecutively received chidamide in combination with anthracycline-based regimen as salvage therapy at the Chinese PLA General Hospital. Of the 27 patients who had received one course of salvage therapy, 13 achieved a complete response and 1 achieved a partial response. We found that the HDAC3-AKT-P21-CDK2 signaling pathway was significantly upregulated in anthracycline-resistant AML cells compared to non-resistant cells. AML patients with higher levels of HDAC3 had lower event-free survival (EFS) and overall survival (OS) rates. Moreover, anthracycline-resistant AML cells are susceptible to chidamide, a histone deacetylase inhibitor which can inhibit cell proliferation, increase cell apoptosis and induce cell-cycle arrest in a time- and dose-dependent manner. Chidamide increases the sensitivity of anthracycline-resistant cells to anthracycline drugs, and these effects are associated with the inhibition of the HDAC3-AKT-P21-CDK2 signaling pathway. Chidamide can increase anthracycline drug sensitivity by inhibiting HDAC3-AKT-P21-CDK2 signaling pathway, thus demonstrating the potential for application.