A novel oxiranylchromenone derivative, MHY336, induces apoptosis and cell cycle arrest via a p53-and p21-dependent pathway in HCT116 human colon cancer cells

In this study, we compared cytotoxicity, cell cycle distribution, and apoptosis on MHY336 treatment in three human colorectal carcinoma HCT116 cells: p53(+/+) (p53-wt), p53(-/-) (p53-null), and p21(-/-) (p21-null), as well as investigated the roles of p53 and p21 in cell death. Using these three isogenic variants, the roles of p53 and p21 in the cellular response to treatment with MHY336, a novel topoisomerase II alpha inhibitor, were investigated. Our results showed that MHY336 treatment increased the expression of p53 over time in cells with wild-type p53 status. This elevated levels of p53 is associated with increased DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase, consistent with increased sensitivity of these cells to apoptotic stimuli. However, p53-null and p21-null cells were more resistant to the antiproliferative and apoptotic effects of MHY336 than p53-wt cells. The same result was achieved by knocking down p53 and p21 with siRNA in p53-wt cells, indicating that p53 and p21 play a crucial role in MHY336-induced cell cycle arrest and apoptosis. Taken together, these results suggest that MHY336 could be a potential candidate to be used in chemoprevention and/or treatment of colon cancer.