Specific therapeutic targeting of liver malignancies by transient depletion of adenosine tri-phosphates

Background & Aims: The current use of TNF in medical oncology is restricted since effective doses lead 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 leading to a TNF resistance (Speicher et al., 2010). In light of the results obtained in the murine system, 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 GI- 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. Conventional methodology for detection of cytotoxicity and caspase activity was adapted to the Precision Cut Tissue Slice technology (PCTS) mimiking tumor patient in vivo conditions. Results: As a basis for the observed tumor selective cytotoxic effect of TNF in the presence of fructose, tumor-selective over¬expression of hexo¬kinase II was detected in tumor cell lines as well as in human primary tumor tissue slices. In a next step, 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. An effect also obvious by treating hepatocytes with chemotherapeutics. Conclusion: These findings revive the possibility for an effective TNF-based regimen towards liver malignancies, by which primary liver tissues are protected by non-toxic doses of fructose while retaining tumor sites keep its sensitivity towards TNF-induced cell death.