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Cellular targeting of the apoptosis-inducing compound gliotoxin to fibrotic rat livers

Lookup NU author(s): Professor Derek Mann, Professor Matthew Wright

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Abstract

Liver fibrosis is associated with proliferation of hepatic stellate cells (HSCs) and their transformation into myofibroblastic cells that synthesize scar tissue. Several studies indicate that induction of apoptosis in myofibroblastic cells may prevent fibrogenesis. Gliotoxin (GTX) was found to induce apoptosis of hepatic cells and caused regression of liver fibrosis. However, the use of apoptosis-inducing drugs may be limited due to lack of cell specificity, with a risk of severe adverse effects. In previous studies, we found that mannose-6-phosphate-modified human serum albumin (M6P-HSA) selectively accumulated in liver fibrogenic cells. The aim of this study therefore was to couple GTX to M6P-HSA and test its pharmacological effects in vitro and in rats with liver fibrosis. The conjugate GTX-M6P-HSA bound specifically to HSCs and reduced their viability. Apoptosis was induced in cultures of human hepatic myofibroblasts (hMFs) and in liver slices obtained from rats with liver fibrosis. In vivo treatment with GTX or GTX-M6P-HSA in bile duct ligated rats revealed a significant decrease in α-smooth muscle actin mRNA levels and a reduced staining for this HSC marker in fibrotic livers. In addition, although GTX also affected hepatocytes, GTX-M6P-HSA did not significantly affect other liver cells. In conclusion, we developed an HSC-specific compound that induced apoptosis in human hMFs, rat HSCs, and in fibrotic liver slices. In vivo, both GTX and GTXM6P-HSA attenuated the number of activated HSCs, but GTX also affected hepatocytes. This study shows that cell-selective delivery of the apoptosis-inducing agent GTX is feasible in fibrotic livers. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.


Publication metadata

Author(s): Hagens WI, Beljaars L, Mann DA, Wright MC, Julien B, Lotersztajn S, Reker-Smit C, Poelstra K

Publication type: Article

Publication status: Published

Journal: Journal of Pharmacology and Experimental Therapeutics

Year: 2008

Volume: 324

Issue: 3

Pages: 902-910

ISSN (print): 0022-3565

ISSN (electronic): 1521-0103

Publisher: American Society for Pharmacology and Experimental Therapeutics

URL: http://dx.doi.org/10.1124/jpet.107.132290

DOI: 10.1124/jpet.107.132290

PubMed id: 18077624


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