title: Differential Antitumoral Properties and Renal-Associated Tissue Damage Induced by Tacrolimus and Mammalian Target of Rapamycin Inhibitors in Hepatocarcinoma: In Vitro and In Vivo Studies.
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.
authors: Institute of Biomedicine of Seville (IBIS), "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville, Seville, Spain.
authors: Elena
authors: E
authors: Navarro-Villarán
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.
authors: José
authors: J
authors: Tinoco
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.
authors: Granada
authors: G
authors: Jiménez
authors: Institute of Biomedicine of Seville (IBIS), "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville, Seville, Spain.
authors: Sheila
authors: S
authors: Pereira
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.
authors: Jize
authors: J
authors: Wang
authors: Institute of Biomedicine of Seville (IBIS), "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville, Seville, Spain.
authors: Sara
authors: S
authors: Aliseda
authors: Institute of Biomedicine of Seville (IBIS), "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville, Seville, Spain.
authors: María A
authors: MA
authors: Rodríguez-Hernández
authors: Institute of Biomedicine of Seville (IBIS), "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville, Seville, Spain.
authors: Raúl
authors: R
authors: González
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.
authors: Luís M
authors: LM
authors: Marín-Gómez
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors: Miguel A
authors: MA
authors: Gómez-Bravo
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors: Francisco J
authors: FJ
authors: Padillo
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors: José M
authors: JM
authors: Álamo-Martínez
authors: Department of General Surgery, "Virgen del Rocío"-"Virgen Macarena" University Hospital/CSIC/University of Seville/IBIS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors: Jordi
authors: J
authors: Muntané
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000068338:Everolimus / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016559:Tacrolimus / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus