一种新型小分子抑制剂的MDM2-p53 (apg - 115)提高辐射敏感度胃腺癌。

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罗易H,燕X, Q,元L,李B,潘W,张L,陈H,王J,张Y,翟Y,邱MZ,杨DJ

一种新型小分子抑制剂的MDM2-p53 (apg - 115)提高辐射敏感度胃腺癌。

J Exp癌症研究杂志2018年5月2日,37 (1):97。doi: 10.1186 / s13046 - 018 - 0765 - 8。

PubMed ID

29716622 (在PubMed

]

文摘

背景:胃癌是全世界癌症相关死亡的主要原因。辐射单独或结合化疗的局部晚期和转移性胃腺癌中发挥了重要的作用。MDM2-p53交互和下游信号影响细胞DNA损伤反应导致细胞周期阻滞和细胞凋亡。因此,恢复p53功能通过抑制与MDM2的互动是一种很有前途的治疗癌症的策略。apg - 115是一种新型小分子抑制剂哪些块MDM2、p53的交互。在这项研究中,我们调查了apg - 115的辐射敏感度在胃腺癌体外和体内。方法:apg - 115的作用在六个胃癌细胞体外由CCK-8决定可行性分析。MDM2的表达水平,p21、彪马和伯灵顿在AGS和MKN45细胞系通过实时多聚酶链式反应(rt - PCR)测定。治疗组的功能在细胞周期和细胞凋亡的检测是通过流式细胞仪测定。单独分析被用来测量辐射敏感度的apg - 115 p53野生型胃癌细胞系。 Western blot was conducted to detect the protein expressions of mdm2-p53 signal pathway. Xenograft models in nude mice were established to explore the radiosensitivity role of APG-115 in gastric cancer cells in vivo. RESULTS: We found that radiosensitization by APG-115 occurred in p53 wild-type gastric cancer cells. Increasing apoptosis and cell cycle arrest was observed after administration of APG-115 and radiation. Radiosensitivity of APG-115 was mainly dependent on MDM2-p53 signal pathway. In vivo, APG-115 combined with radiation decreased xenograft tumor growth much more significantly than either single treatment. Moreover, the number of proliferating cells (Ki-67) significantly decreased in combination group compared with single treatment group. CONCLUSIONS: In summary, we found that combination of MDM2-p53 inhibitor (APG-115) and radiotherapy can enhance antitumor effect both in vitro and in vivo. This is the first report on radiosensitivity of APG-115 which shed light on clinical trial of the combination therapy of radiation with APG-115 in gastric adenocarcinoma.

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