Background: Tacrolimus is a calcineurin inhibitor widely used for immunological disorders.
However, there is significant controversy regarding its effect on the liver. The present study
was conducted to evaluate the anticancer effects of tacrolimus on an induced murine hepatocellular
carcinoma (HCC) model and its possible hepatotoxicity at standard therapeutic doses.
Methods: Fifty-four male mice were divided into five groups: a control healthy group, control
HCC group, tacrolimus-treated group, doxorubicin (DOXO)-treated group, and combined tacrolimus-
and DOXO-treated group. The activity of liver enzymes, including alkaline phosphatase, gamma-
glutamyl transferase, lactate dehydrogenase, alanine transaminase, and aspartate transaminase,
was determined. Serum vascular endothelial growth factor (VEGF) was measured using an enzyme-
linked immunosorbent assay. A quantitative real time- polymerase chain reaction (qRTPCR)
was conducted to measure the expression of proliferating cell nuclear antigen (PCNA), Bax,
and p53 mRNA. Immunohistochemical staining for cyclin D1 and VEGF was performed.
Results: Mice that received combined treatment with tacrolimus and DOXO exhibited the best improvement
in all parameters when compared with the groups that received DOXO or tacrolimus
alone (p < 0.001).
Conclusion: The combination of DOXO and tacrolimus was more effective in the management of
HCC compared with either agent alone. This improvement was detected by the reduction of liver
enzymes and the improvement of the histopathological profile. The involved mechanisms included
significant apoptosis induction demonstrated by upregulation of bax along with a reduction in angiogenesis
demonstrated by downregulation of VEGF. This was accompanied by inhibition of cell
cycle progression mediated by upregulated p53 and downregulated PCNA and cyclin D1.