Suzuki, M., Amano, M., Choi, J. H., Park, H. J., Williams, B. W., Ono, K. and Song, C. W. Synergistic Effects of Radiation and β-Lapachone in DU-145 Human Prostate Cancer Cells In Vitro. Radiat. Res. 165, 525–531 (2006).
It has been reported that β-lapachone (β-lap), a bioreductive anti-cancer drug, synergistically interacts with ionizing radiation and that the sensitivity of cells to β-lap is closely related to the activity of NAD(P)H:quinone oxidoreductase 1 (NQO1). Here we report the results of our studies of mechanisms underlying the synergistic interaction of β-lap and radiation in killing cancer cells using the DU-145 human prostate cancer cell line. The clonogenic cell death caused by the combination of radiation and β-lap was synergistic when β-lap was administered 0–10 h after irradiation but not when it was given before irradiation. The expression and activity of NQO1 increased significantly and remained elevated for longer than 12 h after 4 Gy irradiation, suggesting that the long-lasting elevation of NQO1 sensitized the cells to β-lap. Studies with split-dose irradiation demonstrated that β-lap given immediately after irradiation effectively inhibited sublethal radiation damage (SLD) repair. Taken together, these results lead us to conclude that the synergistic interaction between β-lap and radiation in killing cells is the result of two distinct mechanisms: First, radiation sensitizes cells to β-lap by up-regulating NQO1, and second, β-lap sensitizes cells to radiation by inhibiting SLD repair. The combination of β-lap and radiotherapy is potentially promising modality for the treatment of cancer in humans.