DNA-PKcs plays a great part in classic DNA damage repair pathway. Inhibition of DNA-PKcs is therefore an attractive approach to modulating resistance to therapeutically induced DNA insults. Current cancer therapy invariably utilizes a combination of chemotherapeutic agents and numerous reports have documented the in vitro antiproliferative effect of DNA-PKcs inhibitors [33 - 35]. NU7026 and NU7441, two DNA-PKcs inhibitors, have been clarified to improve the efficacy of various chemotherapeutic drugs, such as etoposide, cisplatin and doxorubicin in some types of solid tumors, including colon cancer, non-small cell lung cancer (NSCLC), leukemia or HCC [36 - 38]. We described here that inhibition of DNA-PKcs by newly-designed inhibitor KU0060648 dose-dependently enhanced the cytotoxic effect of TMZ in glioma cells. Furthermore, the combination of KU0060648 and TMZ could also increase the apoptotic rates. Notably, KU0060648 alone did not enhance the DNA damage in glioma cell lines, suggesting that inhibition of DNA damage repair might not account for, at least not predominant, mechanism that KU0060648 suppressed glioma malignancies.