Novel PI3Kδ inhibitor exerts antitumor activity in Burkitt lymphoma by inducing ROS-dependent apoptosis

Burkitt Lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma characterized by rapid proliferation and extensive systemic dissemination. Challenges persist in treating adult and relapsed/refractory cases, highlighting the need for novel therapeutic approaches. This study aimed to investigate the role of phosphatidylinositol 3-kinase delta (PI3Kδ) in BL pathogenesis and evaluate the therapeutic potential of a selective PI3Kδ Inhibitor, TYM-3-98. The expression of phosphatidylinositol 3-kinase (PI3K)/Akt signaling components in several B-cell lymphoma cell lines was assessed using western blotting. Cell viability and Apoptosis ratio were analyzed using the MTT assay and flow cytometry, respectively, following treatment with PI3Kδ inhibitors. Reactive Oxygen Species (ROS) levels were measured using DCFH-DA staining, followed by microscopy and flow cytometry. The in vivo efficacy of TYM-3-98 against BL was evaluated in BALB/c nude mice by monitoring tumor weight and volume after daily oral administration. Results showed that PI3Kδ is highly expressed in the BL cell lines and is associated with poor prognosis in BL patients. Treatment with TYM-3-98, a specific PI3Kδ Inhibitor, significantly suppressed cell proliferation, induced excessive ROS generation, and triggered caspase-dependent Apoptosis both in vitro and in vivo. Notably, TYM-3-98 demonstrated superior anti-tumor efficacy compared to Idelalisib at equivalent doses, without causing significant weight loss in mice. These findings suggest that PI3Kδ may play a critical role in BL pathogenesis and represents a promising therapeutic target. Further investigation is warranted to advance its clinical application.

Apoptosis; Burkitt Lymphoma; Caspase; PI3K/AKT signaling; PI3Kδ inhibitor; Reactive oxygen species.