Hepatocellular carcinoma is the fifth most common cancer worldwide and shows a complex clinical course, poor response to\npharmacological treatment, and a severe prognosis.Thus, the aim of this study was to investigate whether tacrolimus (FK506) has\nsynergistic antitumor effects with doxorubicin on two human hepatocellular carcinoma cell lines, Huh7 and HepG2. Cell viability\nwas analyzed by Sulforhodamine B assay and synergic effect was evaluated by the software CalcuSyn. Cell apoptosis was evaluated\nusingAnnexinVandDeadCell assay.Apoptosis-related protein PARP-1 cleaved and autophagy-related protein expressions (Beclin-\n1 and LC3B) were measured by western blotting analysis. Cytokines concentration in cellular supernatants after treatments was\nstudied by Bio-Plex assay. Interestingly the formulation with doxorubicin and tacrolimus induced higher cytotoxicity level on\ntumor cells than single treatment. Moreover, our results showed that the mechanisms involved were (i) a strong cell apoptosis\ninduction, (ii) contemporaneous decrease of autophagy activation, understood as prosurvival process, and (iii) downregulation of\nproinflammatory cytokines. In conclusion, future studies could relate to the doxorubicin/tacrolimus combination effects in mice\nmodels bearing HCC in order to see if this formulation could be useful in HCC treatment.
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