الفهرس 
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Abstract
This study aimed to determine the potential therapeutic and/or protective effects of the dual targeting of glutamine by glutamine synthetase inhibitor (MSO) and ammonia by ammonia scavenger (PA) metabolism in vivo in mice with induced HCC and in vitro in the human liver cancer HepG2 cell line.
Relative expression for the GS, mTORC1, β-Catenin, MMP14 genes, and GS concentration was assessed both In vitro and In vivo. Furthermore, In vitro, the HepG2 cell viability, morphology, and cell migration was investigated, and plasma NH3 concentration and serum electrolytes were also measured in the blood of all mice groups. Histopathological examination of liver sections was also performed to assess the effect of treatment on the histology of tumour. Finally, an in-silico study was conducted to further identify potential targets for both MSO and PA that might explaine their anti-cancer effects, individually or in combination.
in vitro, the HepG2 cells where divided into four groups: control, PA-treated, MSO-treated, and PA-MSO-treated. in vivo, the mice were divided into eleven groups: normal, normal-treated with PA, normal-treated with MSO, normal-treated with PA-MSO, pre-treated-PA, pre-treated-MSO, pre-treated-PA-MSO, HCC-induced positive control, therapeutic PA-treated, therapeutic MSO-treated, therapeutic PA-MSO treated.
• Results of the in vitro study:
1. Both PA and MSO showed cytotoxic effects on HepG2 cell line, and a more cytotoxic effect was observed after the combination of the two drugs as demonstrated by the MMT cell-viability assay.
2. Both PA and MSO caused a remarkable morphological alterations to the HepG2 cells, and the greater effect was abserved after exposure to the combination treatment, as demonstrated by the morphological examination of treated cells.
3. The stronger effect for the combination treatment van be evidently explained by the synergism between PA and MSO compared to the individual drugs alone, as demonstrated Compusyn synergism analysis software.
4. Both PA and MSO reduced migration and invasion of HepG2 cells on the cell-culture plates, a greater effect was observed after exposure to a combination of two drugs, as demonstrated in the wound healing assay test.
5. Both PA and MSO and more powerfully the combination treatment caused a significant down-regulation in the expression of the cancer-promoting genes mTORC1, β-catenin, and MMP14, as demonstrated by the RT-PCR.
6. Both PA and MSO and mostly the combination PA+MSO treatment down-regulated GS gene expression and concentration, as demonstrated by both RT-PCR and ELISA techniques, respectively.