A novel iheyamine A derivative L42 suppresses acute myeloid leukemia via dual regulation of the PI3K/AKT/FOXO3a axis and TNF signaling pathway

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies and the development of new drugs is crucial for the treatment of this lethal disease. Iheyamine A is a nonmonoterpenoid azepinoindole alkaloid from the ascidian Polycitorella sp., and its anticancer mechanism has not been investigated in leukemias. Herein, we showed the significant antileukemic activity of L42 in AML cell lines HEL, HL-60 and THP-1. The IC 50 values were 0.466 +/- 0.099 mu M, 0.356 +/- 0.023 mu M, 0.475 +/- 0.084 mu M in the HEL, HL-60 and THP-1 cell lines, respectively, which were lower than the IC 50 (2.594 +/- 0.271 mu M) in the normal liver cell line HL-7702. Furthermore, L42 significantly inhibited the growth of peripheral blood mononuclear cells (PBMCs) from an AML patient. In vivo , L42 effectively suppressed leukemia progression in a mouse model induced by Friend murine leukemia virus (F-MuLV). Mechanistically, we showed that L42 induced cell cycle arrest and apoptosis in leukemia cell lines. RNA sequencing analysis of L42-treated THP-1 cells revealed that the differentially expressed genes (DEGs) were enriched in the cell cycle and apoptosis and predominantly enriched in the PI3K/AKT pathway. Accordingly, L42 decreased the expression of the phospho-PI3K (p85), phospho-AKT and phosphoFOXO3a. Docking and CETSA analysis indicated that L42 bound to the PI3K isoform p110 alpha (PIK3CA), which was implicated in the suppression of the PI3K/AKT pathway. L42 was also shown to initiate the TNF signalingmediated apoptosis. Moreover, L42 exhibited stronger anti-leukemia activity and sensitivity in IDH2-mutant HEL cells than in IDH2-wild-type control. In conclusion, L42 effectively suppresses cell proliferation and triggers apoptosis in AML cell lines in part through inhibition of the PI3K/AKT signaling pathway to restore FOXO3a expression and activation of the TNF signaling pathway. Thus, the iheyamine A derivative L42 represents a novel candidate for AML therapy.