Enhancement of radiation response in human cervical cancer cells in vitro and in vivo by arsenic trioxide (As₂O₃)

Arsenic trioxide (As₂O₃) inhibits cell growth and induces apoptosis in certain types of cancer cells including acute promyelocytic leukemia, prostate and ovarian carcinomas, but its effect on response of tumor cells to ionizing radiation has never been explored before. Here we demonstrate that As₂O₃ can sensitize human cervical cancer cells to ionizing radiation both in vitro and in vivo. As₂O₃ in combination with ionizing radiation have a synergistic effect in decreasing clonogenic survival and in the regression of established human cervical tumor xenografts. Pretreatment of the cells with As₂O₃ also synergistically enhanced radiation-induced apoptosis. Apoptosis of the cells by combined treatment of As₂O₃ and radiation was associated with reactive oxygen species generation and loss of mitochondrial membrane potential, resulting in the activation of caspase-9 and caspase-3. The combined treatment also resulted in an increased G2/M cell cycle distribution at the concentration of As₂O₃ which did not alter cell cycle when applied alone. These results indicate that As₂O₃ can synergistically enhance radiosensitivity of human cervix carcinoma cells in vitro and in vivo, suggesting a potential clinical applicability of combination treatment of As₂O₃ and ionizing radiation in cancer therapies.