Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling
Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling
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DOI：
10.3892/ijo.2012.1735
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发表时间：
2013-02-01
影响因子：
5.2
通讯作者：
Fushiki, Shinji
中科院分区：
文献类型：
--
作者：
Koto, Kazutaka;Murata, Hiroaki;Fushiki, Shinji
唑来膦酸 (ZOL) 是第三代双膦酸盐，可抑制骨吸收，并具有直接的抗肿瘤活性。然而，迄今为止，ZOL 和电离辐射 (IR) 的联合作用尚未在软组织肉瘤患者中进行评估。因此，我们评估了 ZOL 和 IR 对纤维肉瘤细胞的联合作用。用 ZOL 和/或 IR 一起或依次处理 HT1080 纤维肉瘤细胞，并评估抗肿瘤效果。我们发现 ZOL 显着增强 IR 诱导的细胞凋亡，特别是当细胞先用 ZOL 处理，然后再用 IR 处理时。因此，我们评估了 ZOL 和 IR 序贯治疗的详细机制。低浓度的 ZOL 不会增加处于 G2 和 M 期（细胞周期中对放射最敏感的阶段）的细胞。然而，与放射适应性抵抗相关的Akt、ERK1/2和NF-kappa B蛋白的表达水平在3 Gy照射后短时间内增加，并且这种表达被低浓度的ZOL抑制，ZOL阻断了小GTPase的异戊二烯化。这种连续处理还增加了活性氧（ROS）的产生。这些结果表明 ZOL 与 IR 的组合可能有益于治疗软组织肉瘤患者。
Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-kappa 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 ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.