Department of Basic Sciences, Center for Health Disparities Research and Molecular Medicine, Loma Linda University, CA, 92350, USA.
Pancreas. 2009 Oct;38(7):782-90. doi: 10.1097/MPA.0b013e3181a85999.
This study evaluates the efficacy of combining proton irradiation with gemcitabine, and the role the inhibitor of apoptosis proteins survivin and X-linked inhibitor of apoptosis protein (XIAP) play in the radiosensitive versus radioresistant status of pancreatic cancer.
The radioresistant (PANC-1) and radiosensitive (MIA PaCa-2) pancreatic carcinoma cells' response to combined gemcitabine and proton irradiation was compared. Cells were treated with 0.1 to 500 microM gemcitabine and 0- to 15-Gy proton irradiation after which trypan blue and flow cytometry were used to determine changes in the cell cycle and apoptosis. Expression levels of survivin and XIAP were measured using Western blotting. Combination therapy with gemcitabine for 24 hours followed by 10-Gy proton irradiation proved most effective.
Gemcitabine and proton irradiation resulted in increased survivin levels with little apoptosis. However, combination therapy resulted in robust apoptotic induction with a concomitant survivin and XIAP reduction in the MIA PaCa-2 cells with little effect in the PANC-1 cells. Small interfering RNA studies confirmed a role for XIAP in the radioresistance of PANC-1 cells.
Our data demonstrate that combining gemcitabine and proton irradiation enhances apoptosis in human pancreatic cancer cells when XIAP levels decrease. Therefore, XIAP may play an important role in human pancreatic cancer proton radioresistance.
本研究评估了质子放疗联合吉西他滨的疗效，以及凋亡抑制蛋白 survivin 和 X 连锁凋亡抑制蛋白（XIAP）在胰腺癌放射敏感与放射抵抗状态中的作用。
比较了耐辐射（PANC-1）和放射敏感（MIA PaCa-2）胰腺癌细胞对吉西他滨联合质子放疗的反应。用 0.1 至 500μM 吉西他滨和 0 至 15Gy 质子放疗处理细胞，然后用台盼蓝和流式细胞术检测细胞周期和凋亡的变化。用 Western 印迹法测量 survivin 和 XIAP 的表达水平。吉西他滨治疗 24 小时后联合 10Gy 质子放疗效果最佳。
吉西他滨和质子放疗导致 survivin 水平升高，凋亡减少。然而，联合治疗导致 MIA PaCa-2 细胞中凋亡明显诱导，同时 survivin 和 XIAP 减少，但对 PANC-1 细胞影响较小。小干扰 RNA 研究证实 XIAP 在 PANC-1 细胞的放射抵抗中起作用。
我们的数据表明，当 XIAP 水平降低时，吉西他滨和质子放疗联合增强了人胰腺癌细胞的凋亡。因此，XIAP 可能在人胰腺癌细胞的质子放射抵抗中起重要作用。
