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
摘要
鞘氨酸激酶1/2 (SphK1/2)促进乳腺癌的发生和发展。我们利用计算机分子对接技术对SphK抑制剂化合物文库进行筛选,筛选出最具代表性的化合物ZFP-B34,检测其对三阴性乳腺癌(TNBC)的抗肿瘤活性。在TNBC细胞系中,ZFP-B34能有效抑制SphK1/2活性,诱导神经酰胺积累,在不改变SphK1/2表达的情况下导致Sphingosine 1 phosphate (S1P)耗竭,是一种很有前景的新型SphK1/2双抑制剂。ZFP-B34有效抑制细胞增殖、细胞周期进程和迁移,导致细胞生长停滞。ZFP-B34诱导活性氧(ROS)产生和线粒体去极化,导致线粒体功能障碍。同时,它破坏DNA,最终导致细胞凋亡。ZFP-B34还可以抑制akt -哺乳动物雷帕霉素靶蛋白(mTOR)的激活,同时诱导TNBC细胞中c-Jun n -末端激酶(JNK)的激活。在体内,每天腹腔注射单剂量ZFP-B34可有效抑制小鼠4T1同种异体移植物的生长。综上所述,ZFP-B34在体外和体内均能抑制SphK1/2,延缓TNBC细胞的生长。
SphK Inhibitor ZFP-B34 Suppresses the Growth of TNBC Cells.
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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