H2O2 enhances the anticancer activity of TMPyP4 by ROS-mediated mitochondrial dysfunction and DNA damage

Cancer is one of the diseases that threatens human health and is a leading cause of mortality worldwide. High levels of reactive oxygen species (ROS) have been observed in cancer tissues compared with normal tissues in vivo, and it is not yet known how this influences chemotherapeutic drug action. Cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) is a photosensitizer used in photodynamic therapy (PDT) and a telomerase inhibitor used in the treatment of telomerase-positive cancer. Here, we investigated the anticancer activity of TMPyP4 in A549 and PANC cells cultured in H2O2. The results showed that compared to TMPyP4 alone, the combination of TMPyP4 and H2O2 exhibited sensitization effects on cell viability and colony formation inhibition and apoptosis in A549 and PANC cells, but had no effect in human normal MIHA cells. Mechanistically, the combination of TMPyP4 and H2O2 activates high ROS and mitochondrial membrane potential in A549 and PANC cells, resulting in intense DNA damage and DNA damage responses. Consequently, compared to TMPyP4 alone, TMPyP4 and H2O2 combined treatment upregulates the expression of BAX, cleaved caspase 3, and p-JNK and downregulates the expression of Bcl-2 in A549 and PANC cells. Taken together, these data suggested that H2O2 enhanced the anticancer activity of TMPyP4-mediated ROS-dependent DNA damage and related apoptotic protein regulation, revealing that the high ROS tumor microenvironment plays an important role in chemotherapeutic drug action.

Automated summary

The combination treatment of TMPyP4 and H2O2 sensitizes cancer cells to cell death, while having no effect on normal cells. This combination activates high levels of ROS and mitochondrial membrane potential, leading to DNA damage and apoptosis in cancer cells. Furthermore, the treatment upregulates pro-apoptotic proteins and downregulates anti-apoptotic proteins in cancer cells, showcasing the potential of H2O2 to enhance the anticancer activity of TMPyP4.