Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Anticancer Agents Med Chem. 2024;24(20):1501-1513. doi: 10.2174/0118715206345788240902062910.
Due to its high degree of aggressiveness, diffuse large B-cell lymphoma (DLBCL) presents a treatment challenge because 30% to 50% of patients experience resistance or relapse following standard chemotherapy. FN-1501 is an effective inhibitor of cyclin-dependent kinases and Fms-like receptor tyrosine kinase 3.
This study aimed to examine the anti-tumor impact of FN-1501 on DLBCL and clarify its molecular mechanism.
This study used the cell counting kit-8 assay to evaluate cell proliferation, along with western blotting and flow cytometry to analyze cell cycle progression and apoptosis influenced by FN-1501 . Afterward, the effectiveness of FN-1501 was evaluated utilizing the xenograft tumor model. In addition, we identified the potential signaling pathways and performed rescue studies using western blotting and flow cytometry.
We found that FN-1501 inhibited cell proliferation and induced cell cycle arrest and apoptosis in DLBCL cells . Its anti-proliferative effects were shown to be time- and dose-dependent. The effect on cell cycle progression resulted in G1/S phase arrest, and the apoptosis induction was found to be caspase-dependent. FN-1501 treatment also reduced tumor volumes and weights and was associated with a prolonged progressionfree survival . Mechanistically, the MAPK and PI3K/AKT/mTOR pathways were significantly inhibited by FN-1501. Additional pathway inhibitors examination reinforced that FN-1501 may regulate cell cycle arrest and apoptosis through these pathways.
FN-1501 shows promising anti-tumor activity against DLBCL and , suggesting its potential as a new therapeutic option for patients with refractory or relapsed DLBCL.
弥漫性大 B 细胞淋巴瘤（DLBCL）侵袭性高，患者在接受标准化疗后，30%至 50%会出现耐药或复发，因此治疗极具挑战性。FN-1501 是一种有效的细胞周期蛋白依赖性激酶和 Fms 样酪氨酸激酶 3 抑制剂。
本研究旨在探讨 FN-1501 对 DLBCL 的抗肿瘤作用，并阐明其分子机制。
本研究采用细胞计数试剂盒-8 法评估细胞增殖情况，Western blot 和流式细胞术分析 FN-1501 对细胞周期进程和凋亡的影响。随后，利用异种移植肿瘤模型评估 FN-1501 的疗效。此外，我们还通过 Western blot 和流式细胞术鉴定了潜在的信号通路，并进行了挽救研究。
我们发现 FN-1501 抑制 DLBCL 细胞增殖，并诱导细胞周期停滞和凋亡。其抗增殖作用呈时间和剂量依赖性。对细胞周期进程的影响导致 G1/S 期阻滞，凋亡诱导与半胱天冬酶依赖性有关。FN-1501 治疗还可减小肿瘤体积和重量，并延长无进展生存期。机制上，FN-1501 显著抑制 MAPK 和 PI3K/AKT/mTOR 通路。进一步的通路抑制剂检测结果表明，FN-1501 可能通过这些通路调节细胞周期停滞和凋亡。
FN-1501 对 DLBCL 具有良好的抗肿瘤活性，表明其可能成为难治性或复发性 DLBCL 患者的一种新的治疗选择。
