Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma
Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma
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DOI：
10.1269/jrr.06077
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发表时间：
2007-05-01
影响因子：
2
通讯作者：
Oh, Hae Jin
中科院分区：
文献类型：
--
作者：
Kim, Wonwoo;Seong, Jinsil;Oh, Hae Jin
本研究的目的是探讨PI 3 K的特异性抑制剂渥曼青霉素是否可以增强放射在体内的抗肿瘤作用，特别是对放射抗性小鼠肿瘤。用25戈伊照射、渥曼青霉素或两者联合治疗携带同系肝癌（HCa-I）的C3 H/HeJ小鼠。每天一次腹膜内施用渥曼青霉素（lmg/kg），持续14天。通过肿瘤生长延迟测定确定肿瘤对治疗的反应。通过检测细胞凋亡和调节分子的水平，探讨了可能的作用机制。通过蛋白质印迹法检测p53和p21（WAF 1/CIP 1）的表达，并通过免疫组化染色检测p21（WAF 1/CIP 1）、CD 31和VEGF的表达。在肿瘤生长延迟试验中，渥曼青霉素以2.00的增强因子（EF）增加肿瘤放射反应的效果。联合治疗所达到的细胞凋亡水平显示不超过累加效应;单独辐射组的峰值细胞凋亡指数为11%，单独渥曼青霉素组为13%，联合治疗组为19%。在联合组中观察到24 h时坏死面积显著增加。蛋白质印迹显示联合治疗组中p21（WAFI/CIP 1）上调，这与低水平的VEGF相关。基于CD 31的低表达，微血管密度也明显降低。渥曼青霉素可增强放射线对小鼠肝癌的抗肿瘤作用。其机制可能不仅涉及诱导凋亡的增加，而且还涉及血管损伤的增强。Wortmannin与放射疗法结合可能对癌症治疗有潜在的益处。
The objective of this study was to explore whether a specific inhibitor of PI3K, wortmannin, could potentiate the antitumor effect of radiation in vivo, particularly on radioresistant murine tumors. C3H/HeJ mice bearing syngeneic hepatocarcinoma (HCa-I) were treated with 25 Gy radiation, wortmannin, or both. Wortmannin was administered intraperitoneally (1 mg/kg) once daily for 14 days. Tumor response to treatment was determined by a tumor growth delay assay. Possible mechanisms of action were explored by examining the level of apoptosis and regulating molecules. The expression of regulating molecules was analyzed by Western blot for p53 and p21(WAF1/CIP1), and immunohistochemical staining for p21(WAF1/CIP1), CD31 and VEGF. In the tumor growth delay assay, wortmannin increased the effect of tumor radioresponse with an enhancement factor (EF) of 2.00. The level of apoptosis achieved by the combined treatments was shown to be no more than an additive effect; peak apoptotic index was 11% in radiation alone, 13% in wortmannin alone, and 19% in the combination group. Markedly increased areas of necrosis at 24 h in the combination group were noted. Western blotting showed upregulation of p21(WAFI/CIP1) in the combination treatment group, which correlated with low levels of VEGF. Microvascular density was evidently also reduced, based on low expression of CD31. In murine hepatocarcinoma, the antitumor effect of radiation was potentiated by wortmannin. The mechanism seems to involve not only the increase of induced apoptosis but also enhanced vascular injury. Wortmannin, in combination with radiation therapy, may have potential benefits in cancer treatment.