Melatonin improves the AntiHCC Effect of MSCs - Abstract
This study was conducted to investigate the potential therapeutic effect of Melatonin (Mel) and/or mesenchymal stem cells (MSCs) on diethylnitrosamine (DEN)- induced rat model of HCC. Female mature rats were divided into 5 groups (n = 10/group): normal (Nor) group given saline orally for 20 weeks, and HCC group intraperitoneally injected with 200 mg/kg DEN, in addition to 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/1 ml PBS, and HCC + MSCs (Mel +MSCs) group MSCs were pretreated with 5 µM Mel before injection. Rats injected in HCC group showed most deteriorated effect in form of increased mortality and relative liver weight, elevated serum levels of the liver damage enzymes, ALT, AST, and ALP, and the two cancer markers AFP and GGT in addition to increased preneoplastic nodules (altered hepatic foci) in liver tissues. Liver tissues of HCC group also exhibited lower level of apoptosis as indicated by decrease in DNA fragmentation, and downregulated expression of the apoptotic genes p53 and caspase 9. Moreover, in this group the expression of inflammation-related genes (IL6 and TGF?1) was significantly upregulated. All these deleterious effects induced by DEN were reversed after administration of Mel and/ or MSCs with best improvement for the preconditioned group (MSCs+Mel). These findings reveal a better therapeutic effect for MSCs when preconditioned with Mel before injection and we attribute this beneficial effect, at least in part, to induction of apoptosis and inhibition of inflammation in HCC microenvironment. Therefore, pretreatment with Mel is recommended to enhance the therapeutic potential of MSCs for HCC.