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The present study investigated the nuclear transportation phenomenon of 125I-nerve growth factor (NGF) and the DNA-damaging changes to U251 cells using microautoradiography and single cell electrophoresis. The results showed that 125I-NGF inhibited the survival of p53 mutant U251 human glioma cell/tumor and enhanced the therapeutic effectiveness of vincristine in in vivo and in vitro models. In vitro experiments showed 125I-NGF was transported into the nucleus and damaged the DNA in U251 cells. Moreover, 125I-NGF locked the U251 cells in the G2 phase. Further investigation showed that 125I-NGF decreased cyclin B1 protein levels in a dose dependent manner, but the level of cyclin B1 mRNA expression remained unchanged. 125I-NGF increased phosphorylated Chk1, Chk2 and Cdc25c protein levels in U251 cells, but did not influence p53 and p21 protein expression. Moreover, 125I-NGF and vincristine exhibited synergistic effects on reducing cyclin B1 protein levels. These results indicate that 125I-NGF can provide anti-tumor effects by activating the ATM and ATR pathways through DNA damage.