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The Potential Therapeutic Effect for Melatonin and Mesenchymal Stem Cells on Hepatocellular Carcinoma

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The Potential Therapeutic Effect for Melatonin and Mesenchymal Stem Cells on Hepatocellular Carcinoma

Yasser Mohamed et al. Biomedicine (Taipei).

Abstract

Background/aim: Herein, we investigated the potential therapeutic effect of Melatonin (Mel) and/or mesenchymal stem cells (MSCs) on rat model of HCC.

Materials and methods: Female mature rats were divided into 5 groups (n = 10/group): normal (Nor), HCC group intraperitoneally injected with 200 mg/kg DEN, and 3 treated groups; HCC + Mel (Mel) group given Mel intraperitoneally 20 mg/kg, twice a week, HCC + MSCs (MSCs) group intravenously injected by 1 × 106 cells, and HCC + MSCs (Mel +MSCs) group.

Results: Rats in HCC group showed most deteriorated effect in form of increased mortality and relative liver weight, elevated serum levels of ALT, AST, ALP, AFP and GGT in addition to increased pre-neoplastic nodules in liver tissues. Liver tissues of HCC group also exhibited lower level of apoptosis as indicated by decreased DNA fragmentation and expression of p53 caspase 9 and caspase 3 genes and increased PCNA immunoreactivity. Moreover, in this group the expression of IL6 and TGFβ1 genes was significantly upregulated. All these deleterious effects induced by DEN were reversed after administration of Mel and/ or MSCs with best improvement for the combined group (MSCs + Mel).

Conclusions: These findings reveal a better therapeutic effect for MSCs when given with Mel and we attribute this beneficial effect, at least in part, to triggering apoptosis and targeting inflammation in HCC. Therefore, combined treatment with Mel and MSCs is recommended to enhance the therapeutic potential against HCC.

Keywords: Apoptosis; HCC; Inflammation; MSCs; Melatonin.

Figures

Fig. 1
Fig. 1
Effect of Mel and/or MSCs on relative liver weight and serum levels of liver cancer markers and liver enzymes (AST, ALT, ALP). Normal control (Nor), HCC, HCC treated by Mel (Mel), HCC treated by MSCs (MSCs), and HCC treated by Mel and MSCs (Mel + MSCs) rats. Values are expressed as mean ± SEM (n = 7). Values carrying different lower case letter are significantly different at P <0.05.
Fig. 1
Fig. 1
Effect of Mel and/or MSCs on relative liver weight and serum levels of liver cancer markers and liver enzymes (AST, ALT, ALP). Normal control (Nor), HCC, HCC treated by Mel (Mel), HCC treated by MSCs (MSCs), and HCC treated by Mel and MSCs (Mel + MSCs) rats. Values are expressed as mean ± SEM (n = 7). Values carrying different lower case letter are significantly different at P <0.05.
Fig. 2
Fig. 2
Photomicrographs of liver sections stained by H & E in normal (A), HCC (B), Mel (C), MSCs (D), and Mel + MSCS (E) groups. Scale bar = 50 μm.
Fig. 2
Fig. 2
Photomicrographs of liver sections stained by H & E in normal (A), HCC (B), Mel (C), MSCs (D), and Mel + MSCS (E) groups. Scale bar = 50 μm.
Fig. 3
Fig. 3
Photomicrographs of liver sections immuostained with PCNA antibody in normal (A), HCC (B), Mel (C), MSCs (D), and Mel + MSCS (E) groups. Scale bar = 50 μm.
Fig. 3
Fig. 3
Photomicrographs of liver sections immuostained with PCNA antibody in normal (A), HCC (B), Mel (C), MSCs (D), and Mel + MSCS (E) groups. Scale bar = 50 μm.
Fig. 4
Fig. 4
Effect of Mel and/or MSCs on DNA fragmentation as determined by comet assay and on expression of apoptotic genes, p53, caspase 9 and caspase 3, in livers of HCC rats as detected by qPCR. Data presented as fold change from the normal (Nor) control group. Values are expressed as mean ± SEM (n = 7). Values carrying different lower case letters are significantly different at P < 0.05.
Fig. 4
Fig. 4
Effect of Mel and/or MSCs on DNA fragmentation as determined by comet assay and on expression of apoptotic genes, p53, caspase 9 and caspase 3, in livers of HCC rats as detected by qPCR. Data presented as fold change from the normal (Nor) control group. Values are expressed as mean ± SEM (n = 7). Values carrying different lower case letters are significantly different at P < 0.05.
Fig. 5
Fig. 5
Effect of Mel and/or MSCs on expression of inflammation-related genes, IL6, TGFβ1, in livers of HCC rats as detected by qPCR. Data presented as fold change from the normal (Nor) control group. Values are expressed as mean ± SEM (n = 7). Values carrying different lower case letters are significantly different at P < 0.05.
Fig. 5
Fig. 5
Effect of Mel and/or MSCs on expression of inflammation-related genes, IL6, TGFβ1, in livers of HCC rats as detected by qPCR. Data presented as fold change from the normal (Nor) control group. Values are expressed as mean ± SEM (n = 7). Values carrying different lower case letters are significantly different at P < 0.05.

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