Zhang Enjun, Lu Jun, Liu Liying, Liu Lunming, Hu Hongtao, Zheng Fanli, Lou Siyue
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311403, Zhejiang, China.
Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
Med Oncol. 2025 Jun 21;42(7):277. doi: 10.1007/s12032-025-02837-8.
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.
伯基特淋巴瘤（BL）是一种侵袭性很强的B细胞非霍奇金淋巴瘤，其特征是增殖迅速且广泛的全身播散。在治疗成人及复发/难治性病例方面仍存在挑战，这凸显了新型治疗方法的必要性。本研究旨在探讨磷脂酰肌醇3-激酶δ（PI3Kδ）在BL发病机制中的作用，并评估选择性PI3Kδ抑制剂TYM-3-98的治疗潜力。使用蛋白质印迹法评估几种B细胞淋巴瘤细胞系中磷脂酰肌醇3-激酶（PI3K）/AKT信号通路成分的表达。在用PI3Kδ抑制剂处理后，分别使用MTT法和流式细胞术分析细胞活力和凋亡率。使用DCFH-DA染色测量活性氧（ROS）水平，随后进行显微镜检查和流式细胞术分析。通过每天口服给药后监测肿瘤重量和体积，评估TYM-3-98对BL的体内疗效。结果表明，PI3Kδ在BL细胞系中高表达，且与BL患者的不良预后相关。用特异性PI3Kδ抑制剂TYM-3-98治疗，在体外和体内均显著抑制细胞增殖，诱导过量ROS生成，并触发半胱天冬酶依赖性凋亡。值得注意的是，在等效剂量下，TYM-3-98显示出比idelalisib更优的抗肿瘤疗效，且未导致小鼠体重显著减轻。这些发现表明，PI3Kδ可能在BL发病机制中起关键作用，是一个有前景的治疗靶点。有必要进一步研究以推进其临床应用。
