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Natural HDAC-1/8 inhibitor baicalein exerts therapeutic effect in CBF-AML.

ABSTRACT: BACKGROUND:Although targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor-acute myeloid leukemia (CBF-AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug-resistant characteristic. Our purpose is to evaluate the anti-leukemia effects of Baicalein on CBF-AML and clarify its underlying mechanism. METHODS:Enzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT-qPCR were employed to evaluate the distribution of drugs and the change of ATP-binding cassette (ABC) transporter genes. CCK8, Annexin V/PI, and FACS staining certified the effects of Baicalein on cell growth, apoptosis, and differentiation. Duolink and IP assay assessed the interaction between HDAC-1 and ubiquitin, HSP90 and AML1-ETO, and Ac-p53 and CBF?-MYH11. AML cell lines and primary AML cells-bearing NOD/SCID mice models were used to evaluate the anti-leukemic efficiency and potential mechanism of Baicalein in vivo. RESULTS:Baicalein showed HDAC-1/8 inhibition to trigger growth suppression and differentiation induction of AML cell lines and primary AML cells. Although the inhibitory action on HDAC-1 was mild, Baicalein could induce the degradation of HDAC-1 via ubiquitin proteasome pathway, thereby upregulating the acetylation of Histone H3 without promoting ABC transporter genes expression. Meanwhile, Baicalein increased the acetylation of HSP90 and lessened its connection to AML1/ETO, consequently leading to degradation of AML1-ETO in t(8;21)q(22;22) AML cells. In inv(16) AML cells, Baicalein possessed the capacity of apoptosis induction accompanied with p53-mediated apoptosis genes expression. Moreover, CBF?-MYH11-bound p53 acetylation was restored via HDAC-8 inhibition induced by Baicalein contributing the diminishing of survival of CD34+ inv(16) AML cells. CONCLUSIONS:These findings improved the understanding of the epigenetic regulation of Baicalein, and warrant therapeutic potential of Baicalein for CBF-AML.

SUBMITTER: Yu X

PROVIDER: S-EPMC7449246 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Natural HDAC-1/8 inhibitor baicalein exerts therapeutic effect in CBF-AML.

Yu Xiaoxuan X Li Hui H Hu Po P Qing Yingjie Y Wang Xiangyuan X Zhu Mengyuan M Wang Hongzheng H Wang Zhanyu Z Xu Jingyan J Guo Qinglong Q Hui Hui H

Clinical and translational medicine 20200801 4

<h4>Background</h4>Although targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor-acute myeloid leukemia (CBF-AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug-resistant characteristic. Our purpose is to evaluate the anti-leukemia effects of Baicalein on CBF-AML and clarify its underlying mechanism.<h4>Methods</h4>Enzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT-qPCR were empl ...[more]

PMID: 32898337

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Natural HDAC-1/8 inhibitor baicalein exerts therapeutic effect in CBF-AML.

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Natural HDAC-1/8 inhibitor baicalein exerts therapeutic effect in CBF-AML.

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