Homoharringtonine enhances cytarabine induced apoptosis in acute myeloid leukemia by regulating p38 MAPK/H2AX/Mcl-1 axis

Abstract

Abstract Acute myeloid leukemia (AML) is a fatal disease of hematopoietic malignancies and treated with the conventional combination of cytarabine (Ara-C) and daunorubicin (Dau). Homoharringtonine (HHT) is a natural alkaloid obtained from Cephalotaxus species which was used in China for AML combination treatment. Clinically it has been reported HHT plus Ara-C was equally effective as Dau plus Ara-C in some types of AML patients with less toxic effect. We found HHT downregulates Mcl-1, phosphorylates H2AX and induces apoptosis by activating p38 MAPK. Inactivation of p38 through inhibitors and siRNA blocks apoptosis, H2AX phosphorylation and Mcl-1 reduction. HHT enhances Ara-C activation of p38 MAPK signaling pathway, overcoming Ara-C tolerance to cell apoptosis by regulating the p38/H2AX/Mcl-1 axis. 1:4 (M/M) is the optimal ratio of HHT and Ara-C for AML cell synergistic lethality. HHT synergistically induces apoptosis with Ara-C in vitro and prolongs survival of THP-1 xenografts. We provide a new mechanism for AML treatment by regulating p38 MAPK/H2AX/Mcl-1 axis to improve cytarabine therapy.