Threo-2,3-bis-(4-hydroxy-3-methoxyphenyl)-3-methoxypropanol (THMP) Inhibits Bladder Cancer Cell Proliferation via Oxidative Stress-dependent Apoptosis and DNA Damage

Many lignans exhibit antiproliferative effects against cancer cells, but it is rarely reported for <i>threo</i>-2,3-bis-(4-hydroxy-3-methoxyphenyl)-3-methoxypropanol (THMP), an edible red-pepper-derived lignan. This study evaluates the antiproliferative effects and mechanism of THMP against bladder cancer cells (BFTC905 and T24) regarding ATP content and flow cytometry assays in parallel with the presence and absence of <i>N</i>-acetylcysteine (NAC), an oxidative stress inhibitor. THMP suppressed bladder cancer cell viability in the ATP assay, which was reverted by NAC. Regarding flow cytometry, THMP triggered subG1 arrest and enhanced annexin V-affinity intensity. This apoptotic response was further supported by the finding that THMP upregulated the activation of caspases 3, 8, and 9, which is apoptotic signaling. Moreover, oxidative stress was induced by THMP regarding the upregulation of reactive oxygen species (ROS) and mitochondrial superoxide and the exhaustion of glutathione and mitochondrial membrane potential. Regarding <i>γ</i>H2AX and 8-hydroxy-2-deoxyguanosine detection, THMP was confirmed to have DNA damage ability. These mechanisms were alleviated by NAC. Overall, THMP is the first report demonstrating the antiproliferative effect against bladder cancer cells and clarifying its oxidative stress-dependent mechanisms.