Category: Preclinical Development
Purpose: Colorectal cancer is the most common cause of cancer-related death worldwide. Citrus polymethoxyflavonoids (PMFs) have been found to exhibit various biological activities. Here, we evaluated the inhibitory effects and mechanism of a synthetic tangeretin derivative (PMF1) against human colorectal cancer cells.
Methods: Firstly, we evaluated the effect of PMF1 on the viability and the anchorage-independent grow of human colorectal cancer HCT116 cells. PMF1-induced apoptosis was analyzed by cell cytometry to be one of the possible inhibitory mechanism, and the levels of apoptosis-related proteins were further determined. Epigenetics study includes the protein expressions of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), mRNA expressions and DNA methylation levels of tumor suppressing genes, and the interaction between PMF1 and epigenetic modifying enzymes.
Results: We found that PMF1 at 20 and 30 µM can efficiently inhibited the anchorage-independent growth of HCT116 cells. PMF1 decreased the level of Bcl-2 and increased the cleaved forms of caspase-9, caspase-3, and PARP in the HCT116 cells, thereby inducing cell apoptosis. PMF1 also triggered p21 and DLEC1 gene expressions by demethylating their DNA promoter region. PMF1 downregulated DNMT 1 and HDACs 1, 2, and 4/5/9. Moreover, PMF1 showed interactions with DNMTs and HDACs ex vivo, which might inhibit DNMTs and HDACs activity.
Conclusion: These results indicated that PMF1 might inhibit the growth of human colorectal cancer cells by epigenetically upregulating the tumor suppressing genes.