A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance
作者机构：Department of Pharmacological and Pharmaceutical SciencesCollege of PharmacyUniversity of HoustonHoustonTX77204USA Drug Discovery InstituteUniversity of HoustonHoustonTX77204USA Department of Liver Surgery and TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghai200032China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationFudan UniversityShanghai200032China
出 版 物：《Genes & Diseases》 (基因与疾病（英文）)
年 卷 期：2019年第6卷第4期
页 面：419-430页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：W.W. and R.Z. were partially supported by National Institutesof Health (NIH)/National Cancer Institute grants(R01 CA186662 and R01CA214019) W.W. and R.Z. were alsosupported by American Cancer Society (ACS) grant RSG-15-009-01-CDD. R.Z. was also supported by funds for Robert L.Boblitt Endowed Professor in Drug Discovery and researchfunds from College of Pharmacy and University of Houston.J.C., J.F., and X-R. Y. were supported by grants from theNational Natural Science Foundation of China (No.81272389, 81472674, 81502486). The content of this reportis solely the responsibility of the authors, and does notnecessarily represent the official views of the National Institutesof Health or other funding agencies
主 题：CRISPR/Cas9 Hepatocellular carcinoma MDM2 p53-independent Patient-derived xenograft
摘 要：Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma(HCC)and are associated with increased mortality due to this *** MDM2 has been demonstrated to be a valid approach for the treatment of ***,most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding,and have limited efficacy against tumors with mutant or deficient *** the present study,we developed a novel MDM2 inhibitor(termed SP141)that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer *** demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion,independent of ***,SP141 directly binds the MDM2 protein and promotes MDM2 *** inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to *** addition,in orthotopic and patient-derived xenograft models,SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis,without any host ***,the inhibition of MDM2 by SP141 is essential for its anti-HCC *** results provide support for the further development of SP141 as a lead candidate for the treatment of HCC.
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