Simultaneous Inhibition of Mcl-1 and Induction of DNA Damage Accumulation By Chidamide, a Novel Selective HDACi, Potentiates the Cytotoxicity of ABT-199 in Acute Myeloid Leukemia

Acute myeloid leukemia is a heterogeneous hematopoietic neoplasia with a poor clinical outcome despite its treatment have made great progress in recent years. Strategies for targeting Bcl-2 using ABT-199 attract increasing attentions. however, most treatment failure strongly correlates with acquired up-regulation of MCL-1, which become the Achilles's heel of ABT-199 in clinical use. Here we describe low-cytotoxicity dosage of Chidamide (CS055), a novel selective HDACi designed in China, potentiated the cytotoxicity of ABT-199 towards diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, especially those carrying hyperleukocytosis, as well as highly active in vivo in a AML patient-derived xenograft murine model, while sparing normal peripheral blood mononuclear cells. Mechanistically, ABT-199/CS055-induced cytotoxicity was closely associated with inactivation of Mcl-1 and simultaneous induction of DNA damage accumulation. Of note, we also find a superior resensitization activity of CS055 in contrast with Romidepsin. In summary, our findings suggest that CS055 enhance the eliminating activity of ABT-199 towards AML cells, thus implying a highly promising and potent strategy for treatment of relapsed and refractory AML.