In solid
tumors, including
non-small cell lung carcinomas (NSCLC) the existence of radioresistant subpopulations, such as quiescent or hypoxic
tumor cells, is well established, thus posing a critical therapeutic problem. Although small-molecule inhibitors targeting
cyclin-dependent kinases (CDK) were demonstrated to enhance cellular radiosensitivity preferentially in proliferating
tumor cells, cell cycle-independent activities of these substances were recently suggested. In this study, the potential of a newer generation small-molecule CDK inhibitor,
SNS-032, to sensitize radioresistant
tumor cells to ionizing radiation was tested in vitro using two NSCLC cell lines (NCI-H460 and A549). Exposure of quiescent and hypoxic lung
tumor cells to
SNS-032 at a clinically achievable concentration (500 nM) prior to irradiation resulted in a significant increase in cellular radiosensitivity indicating cell cycle-unrelated mechanisms. The effect of
SNS-032 on non-cycling cells was not attributed to an enhanced toxicity of the drug. A
SNS-032 mediated delay in the resolution of radiation-induced gammaH2AX foci a surrogate for
DNA double-strand breaks was determined in non-cycling cells, suggesting a modulation of
DNA double-strand break repair. These results indicate a modulation of
DNA double-strand break repair to be partially attributed to the radiosensitization effects of
SNS-032 observed in hypoxic and quiescent lung
tumor cells. Considering the importance of
therapy resistance for the radiocurability of solid
tumors, our findings may provide the basis for an improvement of the well-established treatment regimens in clinical oncology.