Isosakuranetin lnduces Autophagy and Apoptosis Through AMPK and PI3K/Akt Signaling in Human Leukemia Cells.

Abstract

Background/aim: Leukemia is a group of hematologic malignancies that present considerable therapeutic challenges worldwide. Isosakuranetin, a 4'-O-methylated flavonoid, possesses various biological properties. However, its therapeutic potential against leukemia remains unexplored because of an incomplete understanding of its molecular mechanisms. This study investigated the anticancer effects of isosakuranetin on leukemia cells and elucidated the associated signaling pathways.

Materials and methods: The human leukemia cell lines HL-60 and U937 were treated with serial concentrations of isosakuranetin. Cell viability was evaluated using the Cell Counting Kit-8 assay. Apoptosis and autophagy assays were conducted through annexin V/propidium iodide (PI) staining and acidic vesicular organelle (AVO) staining, respectively. Cell cycle distribution was analyzed through PI staining and flow cytometry. The expression of apoptosis- and autophagy-related proteins in leukemia cells was analyzed using western blotting.

Results: Isosakuranetin exerted distinct regulatory effects on HL-60 and U937 cells over a 48-h treatment period. In HL-60 cells, it increased Beclin-1 expression and suppressed the JNK component of the mitogen-activated protein kinase pathway, up-regulated the PI3K/Akt signaling cascade, and modulated the expression of Bax and Bcl-2. Conversely, in U937 cells, isosakuranetin up-regulated both AMPK/PI3K/Akt and JNK signaling, while down-regulation of Beclin-1 expression. These pathway modulations collectively contributed to the induction of autophagy and apoptosis.

Conclusion: Isosakuranetin induces apoptosis and autophagy in leukemia cells through the AMPK and PI3K/Akt pathways, as well as through JNK activation, with Beclin-1 playing a critical role in their crosstalk. These results highlight the potential of isosakuranetin as a therapeutic agent for leukemia.