Fig. 8Figure 8
Proposed mechanisms for MI-743 induced cell death in gastric cancer cells MGC-803 and HGC-27 through targeting MTH1. In gastric cancer cells MGC-803 and HGC-27(left), increased ROS convert dGTP and dATP to 8-oxo-dGTP and 2-OH-dATP, respectively. The overexpressed MTH1 hydrolyzes the oxidized triphosphates into the corresponding 8-oxo-dGMP and 2-OH-dAMP, in order to prevent their incorporation into double strand DNA and further maintain cancer cell survival. However, under the treatment of compound MI-743(right), the enhanced activity of MTH1 in cancer cells is inhibited. The oxidized nucleotides (8-oxo-dGTP and 2-OH-dATP) will be incorporated into DNA, which further causes double strand DNA damage and finally induces cell death