Yuxingcao formula suppresses acute erythroleukemia through inhibition of AKT1 and FLI1

Abstract

Acute erythroid leukemia (AEL), a rare form of acute myeloid leukemia (AML), is defined as type M6 under the FAB classification, and characterized by inhibition of terminal differentiation and rapid expansion of erythroid progenitors. Despite its poor prognosis, AEL responds well to chemotherapy. Yet, the frequent emergence of resistant clones is a major concern, necessitating the development of alternative therapeutic strategies to treat this rare disease. Yuxingcao formula (YXCF), which consists of 5 herbs, is used in Traditional Chinese Medicine to treat various diseases including cancer, although the underlying mechanisms are not fully understood. Herein, we shown that in an animal model of erythroleukemia induced by Friend virus, YXCF treatment strongly inhibits leukemia progression accompanied by induction of erythroid differentiation, apoptosis and cell cycle arrest. UPLC-MS/MS and network pharmacology analyses of YXCF identified 89 compounds, 20 of which are known to have anti-cancer activity. Molecular docking identified AKT1 as a potential target of one of these compounds, baicalein. In docking and CETSA analyses, baicalein binds AKT leading to inhibition of its phosphorylation and its target mTOR. Baicalein significantly inhibited proliferation of leukemic cells in culture associated with induction of apoptosis and cell cycle arrest as well as suppression of erythroleukemogenesis in vivo. YXCF is also inhibits the FLI1 oncogene, known to play a critical role in erythroleukemia, likely through kaempferol, another YXCF compound. Understanding the role of other components of YXCF may eventually enable the development of a combination drug therapy with optimal anti-leukemia activity for the treatment of AEL.