Identification of Novel Anti-Liver Cancer Small Molecules with Better Therapeutic Index than Sorafenib via Zebrafish Drug Screening Platform

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 estab...

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Bibliographic Details
Published in:Cancers 2019-05, Vol.11 (6), p.739
Main Authors: Lin, Han-Syuan, Huang, Yi-Luen, Wang, Yi-Rui Stefanie, Hsiao, Eugene, Hsu, Tsu-An, Shiao, Hui-Yi, Jiaang, Weir-Torn, Sampurna, Bonifasius Putera, Lin, Kuan-Hao, Wu, Ming-Shun, Lai, Gi-Ming, Yuh, Chiou-Hwa
Format: Article
Language:English
Subjects:
Angiogenesis
Cancer therapies
Danio rerio
Disease
Disease prevention
Drug screening
Drugs
Embryos
Genes
Hepatitis
Hepatocellular carcinoma
Liver cancer
Medical research
Medicine
Patients
Precision medicine
Protein-tyrosine kinase
Proteins
Radiation therapy
Research centers
Signal transduction
Toxicity
Tumors
Vascular endothelial growth factor
Xenografts
Zebrafish
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Summary: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 transgenic embryos and the half inhibition concentration (IC ) was determined. 419S1 exhibited lower hepatoxicity and embryonic toxicity than 420S1 and Sorafenib, and the half lethal concentration (LC ) was determined. The therapeutic index (LC /IC ) 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11060739