Anti-cancer activity of the glycyrrhetinic acid derivatives with an inhibitory inflammatory microenvironment.

The tumor inflammatory microenvironment plays an important role in tumor development, and the compounds which modulate tumor microenvironment can be able to accelerate tumor cell death. Here, compound 1 was screened and evaluated through both inhibiting cancer cell proliferation and alleviating the inflammation in microenvironment. In the anti-cancer cell proliferation assay, compound 1 displayed strong proliferative inhibition against all six cell lines, with IC₅₀ values in the range 2-6 μM; among them, the HCT116 cell line was the most sensitive to compound 1. Second, compound 1 showed better inflammatory activities in RAW264.7 cell model than the control GA and 5-FU; it not only decreased the NO level in a concentration-dependent manner, but also reduced the TLR4, HMGB1, IL-1β, TNF-α, iNOS and COX-2 levels; moreover, compound 1 also strongly inhibited NO produce in A549, HEPG2, and HCT116 cells, and it displayed the best for HCT116 cells, with an IC₅₀ value of 2.04 ± 0.68 μM. Third, compound 1 decreased the MMP and increased ROS levels in HCT116 cells; and it upregulated the expression levels of Bax and Cyt-C, and downregulated the Bcl-2 level, finally activating caspase-3 to promote the HCT116 cells apoptosis. This indicates compound 1 had an anti-HCT116 activity possibly by inhibiting the inflammatory factors in microenvironment, as well as by inducing HCT116 cells apoptosis. In animal tests, compound 1 reduced the volume and weight of tumor, indicating it has an obvious anti-tumor effect. Overall, compound 1 is a multi-target drug for the treatment of colon cancer, and it has the potential to be an anti-colon cancer drug candidate.