Combination of betulinic acid and chidamide inhibits acute myeloid leukemia by suppression of the HIF1α pathway and generation of reactive oxygen species
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Hongyu Zhang1,*, Ling Li2,*, Min Li3, Xiaodong Huang3, Weiguo Xie3, Wei Xiang2 and Paul Yao1,2,3
1Department of Hematology, Peking University Shenzhen Hospital, Shenzhen 518036, P.R. China
2Department of Pediatrics, Maternal and Child Health Care Hospital of Hainan Province, Haikou 570206, P.R. China
3Institute of Burns, Tongren Hospital of Wuhan University, Wuhan 430060, P.R. China
*These authors have contributed equally to this work
Paul Yao, email: email@example.com
Wei Xiang, email: firstname.lastname@example.org
Weiguo Xie, email: email@example.com
Keywords: AHR, AML, HIF1α, reactive oxygen species, VEGF
Received: August 24, 2017 Accepted: September 24, 2017 Published: October 16, 2017
Acute myeloid leukemia (AML) is a heterogeneous disorder of the hematopoietic system with no common genetic “Achilles heel” that can be targeted. Most patients respond well to standard therapy, while a majority relapse, and development of an effective therapy for AML patients is still urgently needed. In this study, we demonstrated that betulinic acid (BA) significantly increased Aryl hydrocarbon receptor (AHR) expression through demethylation on the AHR promoter in AML cells, and the increased AHR expression interacts with and sequesters ARNT, subsequently suppressing hypoxia-inducible factor-1α (HIF1α) pathway. We also found that histone deacetylase inhibitor chidamide (CDM) treatment significantly increased p300 over-acetylation in AML cells with dissociation of p300 with HIF1α, and subsequently suppressed the HIF1α pathway. Further investigation showed that BA/CDM combination additively increased generation of reactive oxygen species (ROS) with DNA damage, apoptosis and mitochondrial dysfunction. Also, BA/CDM combination additively suppressed the HIF1α pathway with decreased VEGF expression. in vivo mice study showed that BA/CDM combination significantly suppressed AML tumor growth, and overexpression of SOD2 and a constitutive HIF1α (HIF1C) completely diminished this effect. We conclude that a BA/CDM combination inhibits AML tumors through ROS over-generation and HIF1α pathway suppression. This is the first time we have shown the potential effect and possible mechanism of BA and CDM on the inhibition of AML tumor growth.
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