Abstract:
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 IC50 values were 0.466±0.099 µM, 0.356±0.023 µM, 0.475±0.084 µM in the HEL, HL-60 and THP-1 cell lines, respectively, which were lower than the IC50 (2.594±0.271 µM) 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 phospho-FOXO3a. Docking and CETSA analysis indicated that L42 bound to the PI3K isoform p110α (PIK3CA), which was implicated in the suppression of the PI3K/AKT pathway. L42 was also shown to initiate the TNF signaling-mediated 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.
摘要:
急性髓系白血病(AML)是最常见的造血系统恶性肿瘤之一,新药的开发对于治疗这种致命疾病至关重要。IheyamineA是来自海鞘Polycitorellasp的非单萜氮杂吲哚生物碱。,其抗癌机制尚未在白血病中进行研究。在这里,我们在AML细胞系HEL中显示了L42的显着抗白血病活性,HL-60和THP-1。IC50值为0.466±0.099µM,0.356±0.023µM,HEL中的0.475±0.084µM,HL-60和THP-1细胞系,分别,低于正常肝细胞系HL-7702的IC50(2.594±0.271µM)。此外,L42显著抑制AML患者外周血单核细胞(PBMC)的生长。在体内,在由Friend鼠白血病病毒(F-MuLV)诱导的小鼠模型中,L42有效抑制白血病进展。机械上,我们发现L42在白血病细胞系中诱导细胞周期阻滞和凋亡。L42处理的THP-1细胞的RNA测序分析表明,差异表达基因(DEG)在细胞周期和凋亡中富集,并且主要在PI3K/AKT途径中富集。因此,L42降低了磷酸-PI3K(p85)的表达,磷酸-AKT和磷酸-FOXO3a。对接和CETSA分析表明L42与PI3K同工型p110α(PIK3CA)结合,这与PI3K/AKT途径的抑制有关。L42还显示启动TNF信号传导介导的细胞凋亡。此外,与IDH2野生型对照相比,L42在IDH2突变型HEL细胞中表现出较强的抗白血病活性和敏感性。总之,L42通过抑制PI3K/AKT信号通路以恢复FOXO3a表达和TNF信号通路的激活,有效抑制AML细胞系中的细胞增殖并触发凋亡。因此,iheyamineA衍生物L42是AML治疗的新候选药物。