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

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

  • Biomed Pharmacother. 2024 Aug:177:117071. doi: 10.1016/j.biopha.2024.117071.
Wang Dinghuan 1,  Kuang Yi 2,  Tian Jianzhi 3,  Wei Wenfei 3,  Wang Chunlin 3,  Hu Anling 3,  He Zhixu 4,  Yaacov Ben-David 5,  Liu Sheng 6,  Yang Xiaoyan 7,  Xiao Xiao 8
Affiliations

Affiliations

  • 1 Department of Pediatrics, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550000, PR China; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550014, PR China; Natural Products Research Center of Guizhou Province, Guiyang, Guizhou 550014, PR China.
  • 2 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550014, PR China.
  • 3 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550014, PR China; Natural Products Research Center of Guizhou Province, Guiyang, Guizhou 550014, PR China.
  • 4 Department of Pediatrics, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550000, PR China.
  • 5 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550014, PR China; Natural Products Research Center of Guizhou Province, Guiyang, Guizhou 550014, PR China. Electronic address: yaacovbendavid@hotmail.com.
  • 6 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550014, PR China; Natural Products Research Center of Guizhou Province, Guiyang, Guizhou 550014, PR China. Electronic address: lsheng@126.com.
  • 7 Department of Pediatrics, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550000, PR China. Electronic address: 469389553@qq.com.
  • 8 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550014, PR China; Natural Products Research Center of Guizhou Province, Guiyang, Guizhou 550014, PR China. Electronic address: kindmexx@163.com.
PMID: 38981243 DOI: 10.1016/j.biopha.2024.117071
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.

Keywords

AML; Iheyamine A; PI3K/AKT/FOXO3a; PIK3CA; TNF-α.

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