表鬼臼素 B 赋予 DAB2IP 基因敲低放射性耐药前列腺癌细胞的辐射增敏作用。
Epothilone B confers radiation dose enhancement in DAB2IP gene knock-down radioresistant prostate cancer cells.
机构信息
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9187, USA.
出版信息
Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):1210-8. doi: 10.1016/j.ijrobp.2010.06.019.
PURPOSE
In metastatic prostate cancer, DOC-2/DAB2 interactive protein (DAB2IP) is often downregulated and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer (PCa). Our preliminary results show that DAB2IP-deficient PCa cells are radioresistant. In this study, we investigated the anticancer drug Epothilone B (EpoB) for the modulation of radiosensitivity in DAB2IP-deficient human PCa cells.
METHODS AND MATERIALS
We used a stable DAB2IP-knock down human PCa cell line, PC3 shDAB2IP, treated with EpoB, ionizing radiation (IR), or the combined treatment of EpoB and IR. The modulation of radiosensitivity was determined by surviving fraction, cell cycle distribution, apoptosis, and DNA double-strand break (DSB) repair. For in vivo studies, the PC3shDAB2IP xenograft model was used in athymic nude mice.
RESULTS
Treatment with EpoB at IC(50) dose (33.3 nM) increased cellular radiosensitivity in the DAB2IP-deficient cell line with a dose enhancement ratio of 2.36. EpoB delayed the DSB repair kinetics after IR and augmented the induction of apoptosis in irradiated cells after G(2)/M arrest. Combined treatment of EpoB and radiation enhanced tumor growth delay with an enhancement factor of 1.2.
CONCLUSIONS
We have demonstrated a significant radiation dose enhancement using EpoB in DAB2IP-deficient prostate cancer cells. This radiosensitization can be attributed to delayed DSB repair, prolonged G(2) block, and increased apoptosis in cells entering the cell cycle after G(2)/M arrest.
目的
在转移性前列腺癌中，DOC-2/DAB2 相互作用蛋白（DAB2IP）通常下调，并已被报道为预测侵袭性前列腺癌（PCa）风险的可能预后标志物。我们的初步结果表明，DAB2IP 缺陷型 PCa 细胞具有放射抗性。在这项研究中，我们研究了埃博霉素 B（EpoB）对 DAB2IP 缺陷型人 PCa 细胞放射敏感性的调节作用。
方法和材料
我们使用稳定的 DAB2IP 敲低人 PCa 细胞系 PC3 shDAB2IP，用 EpoB、电离辐射（IR）或 EpoB 和 IR 的联合治疗进行处理。通过存活分数、细胞周期分布、细胞凋亡和 DNA 双链断裂（DSB）修复来确定放射敏感性的调节。对于体内研究，使用 PC3 shDAB2IP 异种移植模型在裸鼠中进行。
结果
用 IC（50）剂量（33.3 nM）的 EpoB 处理可增加 DAB2IP 缺陷细胞系的细胞放射敏感性，剂量增强比为 2.36。EpoB 延迟 IR 后的 DSB 修复动力学，并在 G（2）/M 期阻滞后照射细胞中增加细胞凋亡的诱导。EpoB 和辐射的联合治疗增强了肿瘤生长延迟，增强因子为 1.2。
结论
我们已经证明了在 DAB2IP 缺陷型前列腺癌细胞中使用 EpoB 可显著增强放射剂量。这种放射增敏作用可归因于 DSB 修复延迟、G（2）期阻滞延长以及 G（2）/M 期阻滞后进入细胞周期的细胞中细胞凋亡增加。
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