Poor prognosis and high lethality of glioma is largely attributed to the high invasion and angiogenesis property of glioma cells [39, 40], which is clinically linked to chemotherapy resistance [41, 42]. These malignant phenotypes essentially support glioma cell proliferation and spreading. Our data demonstrates that KU0060648 effectively inhibited the glioma invasion and angiogenesis in vitro. However, we noticed that administration of 100 μM TMZ slightly promoted these malignant properties of glioma. Such a phenomenon of “chemotherapy induced tumor invasion and angiogenesis” is not a new story in the preclinical literatures, but is often overlooked as a mechanism that may contribute to eventual resistance and disease progression following therapy failure [43, 44]. Several studies have revealed that activation of DNA-PKcs might be a key tone to facilitate cancer cell invasion and angiogenesis, through coordinately regulating the expressions of related effectors or activities of signals [45, 46]. In our study, we discovered that TMZ treatment alone induced the activation of DNA-PKcs, then upregulated the level of downstream effectors. When KU0060648 was added, those adverse effects of TMZ were eliminated and even brought about a synergistic inhibition of glioma invasion and angiogenesis.