Abstract
Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2), being sirolimus only active in Hep3B cell line. Tacrolimus and Everolimus exerted potent antiproliferative properties in Huh 7 and Hep3B in which cells Sirolimus was inactive. Interestingly, Tacrolimus- and Everolimus-dependent G0/G1 cell accumulation occurred as a consequence of drastic reduction in S, as well as in S and G2+M phases, respectively. The in vivo studies support data on the more effective antitumoral properties of Everolimus, eventual risk of pro-angiogenic tumoral properties and nephrotoxicity of Tacrolimus, and pro-proliferative properties of Sirolimus in tumors developed in nude mice.
MeSH terms
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Animals
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Apoptosis / drug effects
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Carcinoma, Hepatocellular / pathology*
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Cell Cycle / drug effects
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Enzyme Inhibitors / adverse effects
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Everolimus / adverse effects
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Everolimus / pharmacology
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Everolimus / therapeutic use
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Fibrosis
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Humans
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Immunosuppressive Agents / adverse effects
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Immunosuppressive Agents / pharmacology
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Immunosuppressive Agents / therapeutic use
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Kidney / drug effects*
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Kidney / pathology
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Liver Neoplasms / pathology*
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Male
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Mice
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Neovascularization, Pathologic / drug therapy
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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Tacrolimus / adverse effects*
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Tacrolimus / pharmacology*
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Tacrolimus / therapeutic use
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Xenograft Model Antitumor Assays*
Substances
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Enzyme Inhibitors
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Immunosuppressive Agents
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Everolimus
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TOR Serine-Threonine Kinases
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Tacrolimus
Grants and funding
The authors thank the Instituto de Salud Carlos III (PI13/00021), Consejería de Innovación, Ciencia y Empresa (CTS-6264) and Consejería de Salud y Bienestar Social (PI13/00025) for their financial support. The authors also thank the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by Instituto de Salud Carlos III and co-financed by European Development Regional Fund "A way to achieve Europe" ERDF for their financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.