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 CBFβ-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, CBFβ-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.
Keywords: ABC transporter genes; CBF-AML; HDAC-1/8 inhibitors; differentiation; natural product.
© 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.