Selective Protection of Human Liver Tissue in TNF-Targeting of Cancers of the Liver by Transient Depletion of Adenosine Triphosphate

Timo Weiland,Sascha Venturelli,Albrecht Wendel,Heike Bantel,Martina Zimmermann,Alfred Königsrainer,Matthias Schwab,Tobias Speicher,Alexander Berger,Kathrin Klein,Ulrich M Lauer,Thomas S Weiss,Martin Schenk,Michael Bitzer,Johannes Haybaeck

doi:10.1371/journal.pone.0052496

Abstract

BackgroundTumor necrosis factor alpha (TNF) is able to kill cancer cells via receptor-mediated cell death requiring adenosine triphosphate (ATP). Clinical usage of TNF so far is largely limited by its profound hepatotoxicity. Recently, it was found in the murine system that specific protection of hepatocytes against TNF's detrimental effects can be achieved by fructose-mediated ATP depletion therein. Before employing this quite attractive selection principle in a first clinical trial, we here comprehensively investigated the interdependence between ATP depletion and TNF hepatotoxicity in both in vitro and ex vivo experiments based on usage of primary patient tissue materials.MethodsPrimary human hepatocytes, and both non-tumorous and tumorous patient-derived primary liver tissue slices were used to elucidate fructose-induced ATP depletion and TNF-induced cytotoxicity.ResultsPHH as well as tissue slices prepared from non-malignant human liver specimen undergoing a fructose-mediated ATP depletion were both demonstrated to be protected against TNF-induced cell death. In contrast, due to tumor-specific overexpression of hexokinase II, which imposes a profound bypass on hepatocytic-specific fructose catabolism, this was not the case for human tumorous liver tissues.ConclusionNormal human liver tissues can be protected transiently against TNF-induced cell death by systemic pretreatment with fructose used in non-toxic/physiologic concentrations. Selective TNF-targeting of primary and secondary tumors of the liver by transient and specific depletion of hepatocytic ATP opens up a new clinical avenue for the TNF-based treatment of liver cancers.

Highlights

Systemic use of the highly potent antineoplastic cytokine tumor necrosis factor (TNF) is highly limited due to the finding that Tumor necrosis factor alpha (TNF)’s pleiotropic functions induce serious systemic side effects, in particular high grade liver toxicity [1,2]
We investigated the possibility to transfer this approach from murine data to the human system with regard to fructose-mediated transient adenosine triphosphate (ATP) depletion and thereby effectuating the selective disarmament of TNF’s destructive hepatocytic properties
Transient depletion of cellular ATP achieved in primary human hepatocytes by using physiological concentrations of fructose

Summary

Introduction

Systemic use of the highly potent antineoplastic cytokine tumor necrosis factor (TNF) is highly limited due to the finding that TNF’s pleiotropic functions induce serious systemic side effects, in particular high grade liver toxicity [1,2]. Hepatocytes (in contrast to their malign counterparts) exhibit protection towards TNF-induced apoptosis [9,10] This biological difference between hepatocytes and malignant cells was ascribed to a transformation-related overexpression of hexokinase II (HKII) leading to a bypass of the hepatocytic-specific fructose catabolism [10]. Clinical usage of TNF so far is largely limited by its profound hepatotoxicity It was found in the murine system that specific protection of hepatocytes against TNF’s detrimental effects can be achieved by fructose-mediated ATP depletion therein. Before employing this quite attractive selection principle in a first clinical trial, we here comprehensively investigated the interdependence between ATP depletion and TNF hepatotoxicity in both in vitro and ex vivo experiments based on usage of primary patient tissue materials

Methods

Results

Conclusion