Strategy to enhance the anticancer efficacy of X-ray radiotherapy in melanoma cells by platinum complexes, the role of ROS-mediated signaling pathways.

Radiotherapy plays an important role in treatment of cancers with low toxicity to the surrounding normal tissues. However, it still fails to eradicate hypoxic tumors due to the occurrence of radioresistance. Therefore, the search for new radiation sensitizers is of great significance. Platinum (Pt) complexes have been identified as potential radiation sensitizers to increase the sensitivity of cancer cells to radiotherapy. In the present study, we have synthesized four Pt complexes containing (2 - benzimidazole [4, 5-f] - [1, 10] phenanthroline) ligand and found that they could effectively enhance the X-ray-induced growth inhibition against A375 human melanoma cells through induction of G2/M cell cycle arrest. In contrast, they showed much lower cytotoxicity toward human normal cells. The complexes also dramatically inhibited the TrxR activity and caused intracellular ROS overproduction, due to the Auger electron effect of heavy metal element under X-ray radiation. Excessive ROS triggered DNA damage and activated downstream signaling pathways, including the phosphorylation of p53 and p38MAPK, and down-regulation of phosphorylated AKT and ERK, finally resulted in increase of radiosensitivity and inhibition of tumor reproduction. Taken together, our results suggest that the synthetic Pt complexes could be further developed as sensitizers of X-ray radiotherapy.