Oleandrin Suppresses the PI3K/AKT Pathway to Inhibit Growth and Induce Apoptosis in T-cell Acute Lymphoblastic Leukemia Cells and Xenograft Mice

Abstract T-cell acute lymphoblastic leukemia (T-ALL) remains a clinical challenge due to its high relapse rate and limited treatment options. This study aimed to investigate the cytotoxic effects of oleandrin on T-ALL and its underlying mechanism to explore novel therapeutic strategies. In human T-ALL cell lines, it inhibited cell growth and induced apoptosis in a dose- and time-dependent manner, with half-maximal inhibitory concentration (IC₅₀) values ranging from 16 to 31 nM. In mouse xenograft models, oleandrin reduced tumor burden and prolonged survival without significant toxicity. Integrated mechanistic studies, including network pharmacology, transcriptomics, and Western blot analysis, indicated that the anti-leukemic effects of oleandrin are associated with suppression of the PI3K/AKT signaling pathway, as evidenced by reduced levels of key proteins such as PIK3CA, phosphorylated AKT (p-AKT), phosphorylated GSK3β (p-GSK3β), c-Myc, Bcl-2, and Bcl-xL. These findings suggest oleandrin is a promising therapeutic candidate for T-ALL, likely through suppression of the PI3K/AKT pathway.