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.

Navarro-Villarán, ElenaTinoco, JoséJiménez, GranadaPereira, SheilaWang, JizeAliseda, SaraRodríguez-Hernández, María AGonzález, RaúlMarín-Gómez, Luís MGómez-Bravo, Miguel APadillo, Francisco JÁlamo-Martínez, José MMuntané, Jordi2016-09-292016-09-292016-08-12Navarro-Villarán E, Tinoco J, Jiménez G, Pereira S, Wang J, Aliseda S, et al. 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. PLoS ONE. 2016; 11(8):e0160979http://hdl.handle.net/10668/2436Journal Article;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.enCalcineurinaCarcinoma hepatocelularDivisión celularLínea celularEverolimusRechazo del injertoHiperbilirrubinemiaHipertensión portalInmunosupresiónRecurrencia neoplásica locaMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Phosphoric Monoester Hydrolases::Phosphoprotein Phosphatases::CalcineurinMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Adenocarcinoma::Carcinoma, HepatocellularMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle::Cell DivisionMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell LineMedical Subject Headings::Phenomena and Processes::Immune System Phenomena::Immune System Processes::Transplantation Immunology::Host vs Graft Reaction::Graft RejectionMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::HyperbilirubinemiaMedical Subject Headings::Diseases::Digestive System Diseases::Liver Diseases::Hypertension, PortalMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::ImmunosuppressionMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver NeoplasmsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Digestive System Surgical Procedures::Liver TransplantationMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, NudeMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Lactones::Macrolides::SirolimusMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Lactones::Macrolides::TacrolimusMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Lactones::Macrolides::Sirolimus::EverolimusMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm Recurrence, LocalDifferential Antitumoral Properties and Renal-Associated Tissue Damage Induced by Tacrolimus and Mammalian Target of Rapamycin Inhibitors in Hepatocarcinoma: In Vitro and In Vivo Studies.research article27518575open access10.1371/journal.pone.01609791932-6203PMC4982663