Tang Yuanfang, Zhong Mengya, Pan Guangchao, Tan Jinshui, Xie Chendi, Jiang Yuelong, Yao Jingwei, Shan Weihang, Lin Jiaqi, Huang Jiewen, Liu Yating, Li Zhifeng, Xu Bing, Zha Jie
Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China.
Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China.
Pharmaceuticals (Basel). 2022 Dec 22;16(1):15. doi: 10.3390/ph16010015.
Transformed follicular lymphoma (t-FL), for which there is no efficient treatment strategy, has a rapid progression, treatment resistance, and poor prognosis, which are the main reasons for FL treatment failure. In this study, we identified a promising therapeutic approach with chiauranib, a novel orally developed multitarget inhibitor targeting VEGFR/Aurora B/CSF-1R. We first determined the cytotoxicity of chiauranib in t-FL cell lines through CCK-8, EdU staining, flow cytometry, and transwell assays. We also determined the killing effect of chiauranib in a xenograft model. More importantly, we identified the underlying mechanism of chiauranib in t-FL tumorigenesis by immunofluorescence and Western blotting. Treatment with chiauranib significantly inhibited cell growth and migration, promoted apoptosis, induced cell cycle arrest in G2/M phase, and resulted in significant killing in vivo. Mechanistically, chiauranib suppresses the phosphorylation level of VEGFR2, which has an anti-t-FL effect by inhibiting the downstream MEK/ERK/STAT3 signaling cascade. In conclusion, chiauranib may be a potential therapy to treat t-FL, since it inhibits tumor growth and migration and induces apoptosis by altering the VEGFR2/ERK/STAT3 signaling pathway.
转化型滤泡性淋巴瘤（t-FL）进展迅速、具有治疗抗性且预后较差，目前尚无有效的治疗策略，这些是滤泡性淋巴瘤治疗失败的主要原因。在本研究中，我们确定了一种有前景的治疗方法，即使用新型口服多靶点抑制剂奇乌拉尼布（chiauranib），它可靶向血管内皮生长因子受体（VEGFR）/极光激酶B（Aurora B）/集落刺激因子1受体（CSF-1R）。我们首先通过细胞计数试剂盒-8（CCK-8）、5-乙炔基-2'-脱氧尿苷（EdU）染色、流式细胞术和Transwell实验确定了奇乌拉尼布在t-FL细胞系中的细胞毒性。我们还确定了奇乌拉尼布在异种移植模型中的杀伤效果。更重要的是，我们通过免疫荧光和蛋白质免疫印迹法确定了奇乌拉尼布在t-FL肿瘤发生中的潜在机制。奇乌拉尼布治疗可显著抑制细胞生长和迁移，促进细胞凋亡，诱导细胞周期在G2/M期停滞，并在体内产生显著的杀伤效果。从机制上讲，奇乌拉尼布可抑制VEGFR2的磷酸化水平，通过抑制下游的丝裂原活化蛋白激酶/细胞外信号调节激酶/信号转导和转录激活因子3（MEK/ERK/STAT3）信号级联反应发挥抗t-FL作用。总之，奇乌拉尼布可能是治疗t-FL的一种潜在疗法，因为它通过改变VEGFR2/ERK/STAT3信号通路来抑制肿瘤生长和迁移并诱导细胞凋亡。
