Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Cancer Sci. 2012 Feb;103(2):203-9. doi: 10.1111/j.1349-7006.2011.02126.x. Epub 2011 Nov 20.
Mesothelioma is an aggressive tumor caused by asbestos exposure, the incidence of which is predicted to increase globally. The prognosis of patients with mesothelioma undergoing conventional therapy is poor. Radiation therapy for mesothelioma is of limited use because of the intrinsic radioresistance of tumor cells compared with surrounding normal tissue. Thus, a novel molecular-targeted radiosensitizing agent that enhances the radiosensitivity of mesothelioma cells is required to improve the therapeutic efficacy of radiation therapy. ZDHHC8 knockdown reduces cell survival and induces an impaired G(2) /M checkpoint after X-irradiation in HEK293 cells. In the present study, we further analyzed the effect of the combination of ZDHHC8 knockdown and X-irradiation and assessed its therapeutic efficacy in mesothelioma models. SiRNA-induced ZDHHC8 knockdown in 211H and H2052 mesothelioma cells significantly reduced cell survival after X-irradiation. In 211H cells treated with ZDHHC8 siRNA and X-irradiation, the G(2) /M checkpoint was impaired and there was an increase in the number of cells with micronuclei, as well as apoptotic cells, in vitro. In 211H tumor-bearing mice, ZDHHC8 siRNA and X-irradiation significantly suppressed tumor growth, whereas ZDHHC8 siRNA alone did not. Immunohistochemical analysis showed decreased cell proliferation and induction of apoptosis in tumors treated with ZDHHC8 siRNA and X-irradiation, but not with ZDHHC8 siRNA alone. These results suggest that ZDHHC8 knockdown with X-irradiation induces chromosomal instability and apoptosis through the impaired G(2) /M checkpoint. In conclusion, the combination of ZDHHC8 siRNA and X-irradiation has the potential to improve the therapeutic efficacy of radiation therapy for malignant mesothelioma.
间皮瘤是一种由石棉暴露引起的侵袭性肿瘤，预计其全球发病率将会增加。接受常规治疗的间皮瘤患者预后较差。由于肿瘤细胞与周围正常组织相比具有内在的放射抗性，因此放射治疗对于间皮瘤的作用有限。因此，需要一种新型的分子靶向放射增敏剂来增强间皮瘤细胞的放射敏感性，从而提高放射治疗的疗效。ZDHHC8 敲低可降低 HEK293 细胞在 X 射线照射后的细胞存活率，并诱导 G2/M 检查点受损。在本研究中，我们进一步分析了 ZDHHC8 敲低与 X 射线照射联合应用的效果，并评估了其在间皮瘤模型中的治疗效果。在 211H 和 H2052 间皮瘤细胞中，siRNA 诱导的 ZDHHC8 敲低可显著降低 X 射线照射后的细胞存活率。在接受 ZDHHC8 siRNA 和 X 射线照射的 211H 细胞中，G2/M 检查点受损，微核细胞和凋亡细胞的数量增加，体外。在 211H 荷瘤小鼠中，ZDHHC8 siRNA 和 X 射线照射可显著抑制肿瘤生长，而单独使用 ZDHHC8 siRNA 则没有。免疫组织化学分析显示，ZDHHC8 siRNA 和 X 射线照射治疗的肿瘤细胞增殖减少，诱导凋亡，但单独使用 ZDHHC8 siRNA 则没有。这些结果表明，ZDHHC8 敲低与 X 射线照射通过受损的 G2/M 检查点诱导染色体不稳定性和细胞凋亡。总之，ZDHHC8 siRNA 联合 X 射线照射有可能提高恶性间皮瘤放射治疗的疗效。
