Specific therapeutic targeting of malignancies of the liver by transient depletion of adenosine triphosphates

Background & aims: Despite its high potency, TNF's current use in medical oncology is restricted since effective doses leading to profound hepatotoxicity. Interestingly, TNF-induced cytotoxicity is known to be a highly ATP-dependent process. In primary murine hepatocytes it was recognized that fructose transiently depletes ATP which is due to a distinct enzyme configuration being specific for hepatocytes leading to a TNF resistance (Speicher et al., 2010). In light of the murine results, the goal of our current study was to find out whether the therapeutic benefits of fructose also apply to the human situation.

Methodology: By investigating human hepatic tumor cell lines, primary human hepatocytes and both non-tumorous and tumorous patient-derived tissue slices, the clinical applicability of this new „TNF organ toxicity sparing“ therapeutic principle was tested. For this purpose, conventional methodology for detection of cytotoxicity was adapted to the Precision Cut Tissue Slice technology (PCTS) mimiking tumor patient in vivo conditions.

Results: Precise timing and dosing of fructose-mediated ATP depletion and its effect towards TNF responsiveness in human hepatocytes in contrast to tumor cell lines was determined. As a basis for the observed tumor selective cytotoxic effect of TNF in the presence of fructose, tumor-selective overexpression of hexokinase II was detected in tumor cell lines as well as in human primary tumor tissue slices.

Further, the tumor patient situation was modelled by examining the cell death-inducing activity of TNF under the influence of a high cellular fructose load in primary human tumor and corresponding liver tissues. As a result, both impaired LDH release and caspase activity revealed a preferential protection towards TNF-induced cell death by fructose-mediated ATP depletion selectively in non-tumorous primary liver tissues. Beside its effect on TNF-induced cell death fructose pretreatment also was found to enable hepatic protection towards chemotherapeutics.

Conclusion: These findings revive the possibility for an effective TNF-based regimen towards liver malignancies, by which primary liver tissue is protected by non-toxic doses of fructose while retaining tumor sensitivity towards TNF-induced cell death.