Therapeutic efficacy of improved α-fetoprotein promoter-mediated tBid delivered by folate-PEI600-cyclodextrin nanopolymer vector in hepatocellular carcinoma.

Abstract

SNPs in human AFP promoter are associated with serum AFP levels in hepatocellular carcinoma (HCC), suggesting that AFP promoter variants may generate better transcriptional activities while retaining high specificity to AFP-producing cells. We sequenced human AFP promoters, cloned 15 different genotype promoters and tested their reporter activities in AFP-producing and non-producing cells. Among various AFP variant fragments tested, EA4D exhibited the highest reporter activity and thus was selected for the further study. EA4D was fused with tBid and coupled with nano-particle vector (H1) to form pGL3-EA4D-tBid/H1. pGL3-EA4D-tBid/H1 could express a high level of tBid while retain the specificity to AFP-producing cells. In a HCC tumor model, application of pGL3-EA4D-tBid/H1 significantly inhibited the growth of AFP-producing-implanted tumors with minimal side-effects, but had no effect on non-AFP-producing tumors. Furthermore, pGL3-EA4D-tBid/H1 could significantly sensitize HCC cells to sorafenib, an approved anti-HCC agent. Collectively, pGL3-EA4D-tBid/H1, a construct with the AFP promoter EA4D and the novel H1 delivery system, can specifically target and effectively suppress the AFP-producing HCC. This new therapeutic tool shows little toxicity in vitro and in vivo and it should thus be safe for further clinical tests.

• Authors: Bao-guang Hu, Li-ping Liu, George G Chen, Cai Guo Ye, Kevin K C Leung, Rocky L K Ho, Marie C Lin, Paul B S Lai
• Journal: Experimental cell research (Exp Cell Res) Vol. 324 Issue 2 Pg. 183-91 (Jun 10 2014) ISSN: 1090-2422 [Electronic] United States
• PMID: 24726886 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• BH3 Interacting Domain Death Agonist Protein
• Cyclodextrins
• alpha-Fetoproteins
• cyclodextrin polymer
• Polyethyleneimine
• Cellulose
• Folic Acid

Topics

• BH3 Interacting Domain Death Agonist Protein (genetics)
• Carcinoma, Hepatocellular (genetics, therapy)
• Cellulose (chemistry)
• Cyclodextrins (chemistry)
• Folic Acid (chemistry)
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage)
• Hep G2 Cells
• Humans
• Liver Neoplasms (genetics, therapy)
• Nanoparticles (chemistry)
• Polyethyleneimine (chemistry)
• Promoter Regions, Genetic (genetics)
• Treatment Outcome
• Tumor Cells, Cultured
• alpha-Fetoproteins (genetics)