Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths worldwide. Sorafenib was the only U.S. Food and Drug Administration (FDA) approved drug for treating advanced HCC until recently, so development of new target therapy is urgently needed. In this study, we established a zebrafish drug screening platform and compared the therapeutic effects of two multiple tyrosine kinase inhibitors, 419S1 and 420S1, with Sorafenib. All three compounds exhibited anti-angiogenesis abilities in immersed fli1:EGFP transgenic embryos and the half inhibition concentration (IC50) was determined. 419S1 exhibited lower hepatoxicity and embryonic toxicity than 420S1 and Sorafenib, and the half lethal concentration (LC50) was determined. The therapeutic index (LC50/IC50) for 419S1 was much higher than for Sorafenib and 420S1. The compounds were either injected retro-orbitally or by oral gavage to adult transgenic zebrafish with HCC. The compounds not only rescued the pathological feature, but also reversed the expression levels of cell-cycle-related genes and protein levels of a proliferation marker. Using a patient-derived-xenograft assay, we found that the effectiveness of 419S1 and 420S1 in preventing liver cancer proliferation is better than that of Sorafenib. With integrated efforts and the advantage of the zebrafish platform, we can find more effective and safe drugs for HCC treatment and screen for personalized medicine.
The antifreeze glycoproteins (AFGPs) 1 are composed of a repeating tripeptide unit (Ala-Thr-Ala) in which the threonine residue is glycosylated with the disaccharide beta-D-Gal-(1-->3)-alpha-D-GalNAc. A new procedure for synthesizing AFGPs using Fmoc-(Ac4-beta-D-Gal-(1-->3)-benzylidene- alpha-D-GalNAc)Thr-OH (10) as a building block has been developed. Total synthesis of the AFGPs (n = 4, 8) in overall yields of 61% and 33 %, respectively, has demonstrated the usefulness of the method. The synthetic AFGPs 1 (n = 4, 8) showed a similar conformation to the native AFGPs in their circular dichroism spectra.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.