Development of new treatments against malignant bone and soft tissue tumors by using bisphosphonate and ionizing radiation

用第三代双膦酸盐（bp）和/或电离辐射（IR）一起或依次治疗纤维肉瘤细胞，并评估抗肿瘤效果。bp显著增强了IR诱导的细胞凋亡，尤其是bp后IR处理的细胞。因此，我们评估了bp和IR顺序治疗的详细机制。低浓度bp对细胞周期中对辐射最敏感的G2期和M期细胞无明显影响。然而，在3gy辐照后短时间内，与放射适应抗性相关的Akt、ERK1/2和NF- B蛋白的表达水平升高，低浓度bp阻断了小gtpase的戊酰化，从而抑制了这种表达。这种顺序处理也增加了活性氧（ROS）的产生。

Fibrosarcoma cells were treated with third-generation bisphosphonate (BPs) and/or ionizing radiation (IR), together or sequentially, and the antitumor effects were assessed. BPs significantly enhanced IR-induced apoptosis, especially when cells were treated with BPs followed by IR. We therefore assessed the detailed mechanism of sequential treatment with BPs and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of BPs. However, the levels of expression of Akt, ERK1/2, and NF- B proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of BPs, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS).