Author:
Tan Jinshui,Zhong Mengya,Hu Yanyan,Pan Guangchao,Yao Jingwei,Tang Yuanfang,Duan Hongpeng,Jiang Yuelong,Shan Weihang,Lin Jiaqi,Liu Yating,Huang Jiewen,Zheng Huijian,Zhou Yong,Fu Guo,Li Zhifeng,Xu Bing,Zha Jie
Abstract
AbstractRefractory or relapsed (R/R) AML is the most challenging form of AML to treat. Due to frequent genetic mutations, therapy alternatives are limited. Here, we identified the role of ritanserin and its target DGKα in AML. Several AML cell lines and primary patient cells were treated with ritanserin and subjected to cell proliferation, apoptosis and gene analyses with CCK-8 assay, Annexin V/PI assay and Western blotting, respectively. We also evaluated the function of the ritanserin target diacylglycerol kinase alpha (DGKα) in AML by bioinformatics. In vitro experiments have revealed that ritanserin inhibits AML progression in a dose- and time-dependent manner, and it shows an anti-AML effect in xenograft mouse models. We further demonstrated that the expression of DGKα was elevated in AML and correlated with poor survival. Mechanistically, ritanserin negatively regulates SphK1 expression through PLD signaling, also inhibiting the Jak-Stat and MAPK signaling pathways via DGKα. These findings suggest that DGKα may be an available therapeutic target and provide effective preclinical evidence of ritanserin as a promising treatment for AML.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Fujian Province
Xiamen Municipal Bureau of Science and Technology
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Endocrine and Autonomic Systems,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism
Reference40 articles.
1. Thol F, Ganser A. Treatment of relapsed acute myeloid leukemia. Curr Treat Options Oncol. 2020;8:66. https://doi.org/10.1007/s11864-020-00765-5.
2. Ganzel C, Sun Z, Cripe LD, Fernandez HF, Douer D, Rowe JM, et al. Very poor long-term survival in past and more recent studies for relapsed AML patients: the ECOG-ACRIN experience. Am J Hematol. 2018;8:1074–81. https://doi.org/10.1002/ajh.25162.
3. Megias-Vericat JE, Martinez-Cuadron D, Sanz MA, Montesinos P. Salvage regimens using conventional chemotherapy agents for relapsed/refractory adult AML patients: a systematic literature review. Ann Hematol. 2018;7:1115–53. https://doi.org/10.1007/s00277-018-3304-y.
4. Ma J, Ge Z. Recent advances of targeted therapy in relapsed/refractory acute myeloid leukemia. Bosn J Basic Med Sci. 2021;4:409–21. https://doi.org/10.17305/bjbms.2020.5485.
5. Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PF, Laduron PM. Receptor-binding properties in vitro and in vivo of ritanserin: a very potent and long acting serotonin-S2 antagonist. Mol Pharmacol. 1985;6:600–11.
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献