article · Biomedicine & Pharmacotherapy
Treating hepatocellular carcinoma with mesenchymal stem cells often involves preconditioning the cells with melatonin to boost their potency. Administering melatonin directly to the recipient prior to transplanting untreated stem cells offers an alternative strategy to alter the tumour microenvironment. In a rat model of chemically induced liver cancer, providing melatonin before standard stem cell delivery achieved better therapeutic results than using melatonin-preconditioned stem cells. This treatment protocol lowered key liver tumour biomarkers and reduced preneoplastic lesions. It also stimulated programmed cell death in cancer cells by activating pro-apoptotic pathways. In addition, the sequential regimen enhanced antioxidant enzyme levels, decreased oxidative stress, and suppressed genetic indicators linked to inflammation, blood vessel growth, and tumour metastasis. Conditioning the host system with melatonin before cell transplantation helps foster stem cell survival and enhances anti-cancer outcomes.
Liver cancer is challenging to treat, and the efficacy of stem cell therapies can be limited by hostile tumour conditions. Showing that treating the host with melatonin prepares a more receptive microenvironment helps stem cells function more effectively. This finding provides a practical strategy for refining cell therapies and improving therapeutic outcomes in chronic liver malignancies.
This research could inform the development of combination oncology protocols for biotechnology firms and pharmaceutical developers focusing on cell-based therapies. The prospective users would be clinical oncologists and cell therapy providers. Because the findings are derived exclusively from early-stage animal studies in rats, the approach remains far from real-world medical use and requires extensive translational testing and clinical trials.
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Pretreatment of mesenchymal stem cells (MSCs) with melatonin (Mel) improves their potential therapeutic effect on chronic diseases and cancers. However, this preconditioning strategy may direct the effect of Mel toward MSCs alone and deprive cancer cells of the oncostatic effect of Mel. Herein, we hypothesized that Mel given before transplantation of non-preconditioned MSCs may maximize the therapeutic outcome via the oncostatic effect of Mel by preparing a suitable tumor microenvironment for MSCs. Female rats (n = 60) were equally divided into 6 groups; normal control, diethylnitrosamine (DEN), DEN + Mel, DEN + MSCs, DEN + MSCs preconditioned with Mel, and DEN + MSCs + Mel. The obtained data revealed that administration of Mel before MSCs treatment without preconditioning yielded a better ameliorative effect against DEN-induced hepatocellular carcinoma (HCC) as evidenced by: 1) reduced serum levels of alpha fetoprotein and gamma-glutamyl transferase; 2) decreased number and area of glutathione S-transferase placental positive foci; 3) induced apoptosis (as indicated by increased cleaved caspase-3 activity, upregulated expression of proapoptotic genes Bax and caspase 3 and downregulated expression of anti-apoptotic genes Bcl2, survivin); 4) decreased malondialdehyde level and increased activities of superoxide dismutase, catalase, and glutathione peroxidase enzymes; and 5) reduced inflammation, angiogenesis and metastasis as indicated by downregulated expression of interleukin 1 beta, nuclear factor kappa B, vascular endothelial growth factor, and matrix metallopeptidase 9 genes and upregulated expression of metalloproteinase inhibitor 1 gene. Thus, administration of Mel before MSCs (without preconditioning) fostered the survival and therapeutic potential of MSCs in HCC, possibly through induction of apoptosis and inhibition of inflammation and oxidative stress. This new strategy showed better therapeutic outcomes and may improve MSC-based therapies for HCC.
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DOI: 10.1016/j.biopha.2019.108732
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