Synergistic Effects of Radiation and β-Lapachone in DU-145 Human Prostate Cancer Cells In Vitro

Abstract 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.

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