Abstract
The immune system plays a critical role in exerts effects in the growth and progression of hepatocellular carcinoma (HCC), which needs interacting approaches for effective therapy. In this study, we have found that the Norcantharidin (NCTD) + Coix lacryma-jobi seed oil (CLSO) combination exhibited more potent antitumor effects in an terms of cytotoxicity and apoptotic induction in human HepG2 and HepG2/ADM cells than NCTD or CLSO alone. In vivo, administration of NCTD+CLSO combinations significantly suppressed the formation of tumor in Hepal-1 hepatoma-bearing mice. Furthermore, we found that the in vitro co-cultures of HepG2 or HepG2/ADM cells with PBMCs from healthy donors led to an increase in the number of CD4+CD25+ T cells. This increase was down-regulated by the combination effectively. Down-regulation of FoxP3 mRNA and protein expression occurred during the combination in the co-cultures. The amount of Tregs of Hepal-1 hepatoma-bearing mice was significantly decreased in the combination treated group. The combination down-regulated the expression of FoxP3, CTLA-4 and Tregs related cytokine (TGF-β and IL-10) in the serum of tumor bearing mice. Taken together, these results suggest that the most valuable aspect of the NCTD+CLSO combined use improves the anti-tumor activity and regulates tumor infiltrating Tregs.
Highlights
It has been found that CD4+ CD25+ regulatory T cells (Tregs), myeloid derived suppressor cells, and various immunosuppressive factors, including interleukin 10 (IL-10), transforming growth factor β (TGF-β), vascular endothelial growth factor, and prostaglandin E2, are frequently enriched in the tumor microenvironment and facilitate tumor immune evasion[5]
Our results showed that combination with Coix lacryma-jobi seed oil (CLSO) significantly enhanced NCTD efficacy with higher IC50 value of 3.75/ 49.98 (HepG2), 4.48/59.77 (HepG2/ADM) μg/mL (Fig. 1c) and exhibited synergistic effects for HepG2 and HepG2/ADM cells (Table 1)
In the present study, we investigated whether the combinations of NCTD+CLSO led to more superior antitumor effects than NCTD or CLSO alone in hepatocellular carcinoma (HCC) cells
Summary
It has been found that CD4+ CD25+ regulatory T cells (Tregs), myeloid derived suppressor cells, and various immunosuppressive factors, including interleukin 10 (IL-10), transforming growth factor β (TGF-β), vascular endothelial growth factor, and prostaglandin E2, are frequently enriched in the tumor microenvironment and facilitate tumor immune evasion[5]. Antagonizing immunosuppressive mechanisms in the tumor microenvironment are a prerequisite for the translation of antitumor immune responses into therapeutic benefits[6]. Norcantharidin (NCTD) and Coix lacryma-jobi seed oil (CLSO) have already been developed for antitumor clinical applications[9,10,11]. All the results obtained strongly supported the new combination of NCTD and CLSO shows the better therapeutic effect
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