Work

Selective induction of apoptosis in T-cell acute lymphoblastic leukemia by pristimerin through dual PI3K/AKT pathway inhibition and ROS generation

Year: 2025

Type: article

Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by the aberrant activation of survival pathways, particularly the PI3K/AKT axis. Pristimerin (Prist), a naturally occurring quinonemethide triterpenoid, has recently gained attention for its anti-cancer potential. In this study, we demonstrate that Prist effectively inhibits the proliferation of T-ALL cell lines (Jurkat and Molt 4) by inducing G0/G1 cell cycle arrest and triggering intrinsic and extrinsic caspase-dependent apoptosis. Prist significantly increases reactive oxygen species (ROS) levels and depletes glutathione (GSH), leading to mitochondrial dysfunction and cytochrome c release. Notably, ROS scavenging with N-acetylcysteine (NAC) abrogated Prist-induced apoptosis, highlighting ROS as a critical mediator of its cytotoxicity. Network pharmacology and molecular docking revealed AKT as a key target of Prist, with strong binding affinity confirmed through docking analysis. Prist downregulated phosphorylated AKT and inhibitor of apoptosis proteins (XIAP, cIAP1/2), supporting its pro-apoptotic mechanism. Importantly, Prist inhibited the proliferation and AKT phosphorylation in activated primary human T cells but spared resting T cells, indicating selective cytotoxicity. These findings establish Prist as a promising therapeutic candidate for T-ALL through the selective targeting of PI3K/AKT-driven survival signaling.

Source: European Journal of Pharmacology

DOI: 10.1016/j.ejphar.2025.178329