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Published on: July 12, 2018
Cellular targeting of the apoptosis-inducing compound gliotoxin to fibrotic rat livers
W I Hagens1, L Beljaars, D A Mann
1Department of Pharmacokinetics and Drug Delivery, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
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 alpha-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 GTX-M6P-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.
Insights
Researchers developed a targeted therapy for liver fibrosis by linking the apoptosis-inducing drug gliotoxin (GTX) to a liver cell-targeting molecule (M6P-HSA). This novel compound selectively eliminates fibrotic liver cells, offering a promising treatment strategy with reduced side effects.
Area of Science:
- Hepatology
- Pharmacology
- Cell Biology
Background:
- Liver fibrosis involves hepatic stellate cell (HSC) proliferation and myofibroblast transformation, leading to scar tissue synthesis.
- Inducing apoptosis in myofibroblastic cells is a potential strategy to prevent fibrogenesis.
- Gliotoxin (GTX) induces apoptosis and regresses liver fibrosis, but lacks cell specificity, posing risks of adverse effects.
Purpose of the Study:
- To develop a targeted delivery system for GTX to selectively induce apoptosis in liver fibrogenic cells.
- To conjugate GTX with mannose-6-phosphate-modified human serum albumin (M6P-HSA) for selective targeting of HSCs.
- To evaluate the in vitro and in vivo efficacy of GTX-M6P-HSA in liver fibrosis models.
Main Methods:
- Conjugation of GTX to M6P-HSA to create GTX-M6P-HSA.
- In vitro assessment of GTX-M6P-HSA's effect on human hepatic myofibroblasts (hMFs) and rat liver slices.
- In vivo studies using bile duct ligated rats to evaluate GTX and GTX-M6P-HSA treatment.
- Analysis of alpha-smooth muscle actin (SMA) mRNA levels and protein expression as markers for HSC activation.
Main Results:
- GTX-M6P-HSA specifically bound to HSCs and reduced their viability.
- Apoptosis was induced in hMFs and fibrotic liver slices by GTX-M6P-HSA.
- In vivo, both GTX and GTX-M6P-HSA reduced alpha-SMA levels in fibrotic livers.
- GTX-M6P-HSA demonstrated greater cell specificity compared to GTX, sparing hepatocytes.
Conclusions:
- GTX-M6P-HSA is an effective HSC-specific compound that induces apoptosis in fibrogenic liver cells.
- Cell-selective delivery of GTX via M6P-HSA is a feasible approach to treat liver fibrosis.
- This targeted strategy minimizes off-target effects observed with non-specific GTX administration.
