Suzuki Minoru, Amano Morikazu, Choi Jihyung, Park Heon Joo, Williams Brent W, Ono Koji, Song Chang W
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Radiat Res. 2006 May;165(5):525-31. doi: 10.1667/RR3554.1.
It has been reported that beta-lapachone (beta-lap), a bioreductive anti-cancer drug, synergistically interacts with ionizing radiation and that the sensitivity of cells to beta-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 beta-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 beta-lap was synergistic when beta-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 beta-lap. Studies with split-dose irradiation demonstrated that beta-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 beta-lap and radiation in killing cells is the result of two distinct mechanisms: First, radiation sensitizes cells to beta-lap by up-regulating NQO1, and second, beta-lap sensitizes cells to radiation by inhibiting SLD repair. The combination of beta-lap and radiotherapy is potentially promising modality for the treatment of cancer in humans.
据报道，生物还原抗癌药物β-拉帕醌（β-lap）与电离辐射具有协同相互作用，并且细胞对β-lap的敏感性与NAD(P)H：醌氧化还原酶1（NQO1）的活性密切相关。在此，我们报告了我们利用DU-145人前列腺癌细胞系对β-lap与辐射协同杀伤癌细胞的潜在机制的研究结果。当在照射后0-10小时给予β-lap时，辐射与β-lap联合引起的克隆源性细胞死亡具有协同作用，但在照射前给予则无协同作用。4 Gy照射后，NQO1的表达和活性显著增加，并在12小时以上保持升高，这表明NQO1的持久升高使细胞对β-lap敏感。分次照射研究表明，照射后立即给予β-lap可有效抑制亚致死性辐射损伤（SLD）修复。综上所述，这些结果使我们得出结论，β-lap与辐射在杀伤细胞方面的协同相互作用是两种不同机制的结果：第一，辐射通过上调NQO1使细胞对β-lap敏感；第二，β-lap通过抑制SLD修复使细胞对辐射敏感。β-lap与放射治疗的联合应用可能是一种有前景的人类癌症治疗方式。
