TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate-induced growth inhibition in pancreatic cancer cells

Abstract

Chemotherapy and radiotherapy are the most common approaches in cancer therapy. They may kill cancer cells through the generation of high levels of reactive oxygen species (ROS), which leads to oxidative DNA damage. However, tumor resistance to ROS is a problem in cancer therapy. MTH1 sanitizes oxidized dNTP pools to prevent the incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, cancer cells require MTH1 activity to avoid the incorporation of oxidized dNTPs, which would result in DNA damage and cell death. By targeting a redox-adaptation mechanism, MTH1 inhibition represents a novel therapeutic strategy against cancer. However, recent reports have indicated that growth inhibition by MTH1 inhibitors may be due to off-target cytotoxic effects. TH588, one of the first-in-class MTH1 inhibitors, kills cancer cells by an off-target effect. However, a low concentration of TH588 may effectively inhibit MTH1 activity without inhibiting cell proliferation. Phenethyl isothiocyanate (PEITC) is a dietary anticarcinogenic compound and an inducer of ROS. In the present study, it has been demonstrated that combined treatment with PEITC and TH588 effectively inhibited the growth of pancreatic cancer MIAPaCa-2 and Panc-1 cells. The antioxidant N-acetylcysteine negated this synergistic growth inhibition. PEITC and TH588 cooperatively induced the formation of 8-oxo-deoxyguanine in nuclei and pH2AX foci, a marker of DNA damage. However, the combined effects are not associated with MTH1 mRNA expression in several cancer cell lines, suggesting that the possibility of an off-target effect of TH588 cannot be eliminated. These results suggest that the combination of PEITC and TH588 has potential as a novel therapeutic strategy against pancreatic cancer.