Anticancer Effects of Tacrolimus on Induced Hepatocellular Carcinoma in Mice.
Animals
Carcinoma, Hepatocellular
/ drug therapy
Cyclin D1
/ metabolism
Doxorubicin
/ pharmacology
Liver Neoplasms
/ drug therapy
Male
Mice
Proliferating Cell Nuclear Antigen
/ metabolism
Tacrolimus
/ pharmacology
Tumor Suppressor Protein p53
Vascular Endothelial Growth Factor A
/ genetics
bcl-2-Associated X Protein
/ metabolism
ELISA
Hepatocellular carcinoma
anticancer effects
doxorubicin
mice
tacrolimus
Journal
Current molecular pharmacology
ISSN: 1874-4702
Titre abrégé: Curr Mol Pharmacol
Pays: United Arab Emirates
ID NLM: 101467997
Informations de publication
Date de publication:
2022
2022
Historique:
received:
06
10
2020
revised:
12
02
2021
accepted:
17
02
2021
pubmed:
2
6
2021
medline:
25
5
2022
entrez:
1
6
2021
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 34061012
pii: CMP-EPUB-115887
doi: 10.2174/1874467214666210531164546
doi:
Substances chimiques
Proliferating Cell Nuclear Antigen
0
Tumor Suppressor Protein p53
0
Vascular Endothelial Growth Factor A
0
bcl-2-Associated X Protein
0
Cyclin D1
136601-57-5
Doxorubicin
80168379AG
Tacrolimus
WM0HAQ4WNM
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
434-445Informations de copyright
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