Bingqing Cui, Jianming Wei, Huiting Peng, Ting Xu, Mengfei Chen, Yuchen Zhao, Hanshuang Cai, Bo Liu, Jing Shi
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引用次数: 0
Abstract
Sphingosine kinase 1/2 (SphK1/2) promote the initiation and advancement of breast cancers. We performed screening on a compound library of SphK inhibitors using computer molecular docking and selected the most representative compound, ZFP-B34, for testing its antitumor activity in triple-negative breast cancer (TNBC). In TNBC cell lines ZFP-B34 effectively inhibits SphK1/2 activity, induces ceramide accumulation, and results in Sphingosine 1 phosphate (S1P) depletion without altering SphK1/2 expression in TNBC cells, making it a promising novel dual inhibitor of SphK1/2. ZFP-B34 effectively inhibits cell proliferation, cell cycle progression, and migration, leading to cellular growth arrest. ZFP-B34 induces reactive oxygen species (ROS) production and mitochondrial depolarization, leading to mitochondrial dysfunction. Simultaneously, it damages DNA, ultimately resulting in apoptosis. ZFP-B34 can also inhibit the activation of Akt-mammalian target of rapamycin (mTOR) while inducing c-Jun N-terminal kinase (JNK) activation in TNBC cells. In vivo, daily intraperitoneal injection of a single dose of ZFP-B34 effectively inhibits the growth of 4T1 allografts in mice. In conclusion, ZFP-B34 is capable of inhibiting SphK1/2 and delaying the growth of TNBC cells both in vitro and in vivo.
期刊介绍:
Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012.
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