Arsenic sulfide, the main component of realgar, a traditional Chinese medicine, induces apoptosis of gastric cancer cells in vitro and in vivo.
Arsenic sulfide, the main component of realgar, a traditional Chinese medicine, induces apoptosis of gastric cancer cells in vitro and in vivo.
复制标题
中药雄黄的主要成分硫化砷在体外和体内诱导胃癌细胞凋亡
DOI：
10.2147/dddt.s74379
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Zhang L;Tian W;Kim S;Ding W;Tong Y;Chen S
研究背景硫化砷（As 4S 4）是中药雄黄的主要成分，对多种肿瘤，尤其是急性早幼粒细胞白血病有较好的抗肿瘤作用。本研究旨在探讨As 4S 4对胃癌的治疗作用及其机制。方法采用MTT法、4′，6-二脒基-2-苯基吲哚（DAPI）染色法和Annexin V-异硫氰酸荧光素/碘化丙啶染色法，观察As 4S 4对胃癌细胞株AGS（野生型p53）和MGC 803（突变型p53）增殖和凋亡的影响。免疫印迹法、实时荧光定量聚合酶链反应和免疫组织化学分析检测凋亡相关蛋白的表达。接种MGC 803细胞建立小鼠异种移植瘤模型，分别采用苏木精-伊红染色法和原位末端标记法（TUNEL）检测肿瘤组织的形态和凋亡细胞比例。结果As 4S 4可抑制AGS和MGC 803细胞增殖并诱导其凋亡，且呈时间和剂量依赖性。As 4S 4可上调Bax和MDM 2的表达，下调Bcl-2的表达。p53的表达在AGS细胞中显著增加，但在携带突变型p53的MGC 803细胞中不容易增加。p53抑制剂Pifithrin-α可阻断As 4S 4对AGS细胞的调节作用，但对MGC 803细胞无影响。以异种移植瘤为模型，我们发现As 4S 4在体内抑制肿瘤生长并诱导细胞凋亡，p53的表达相应增加。结论As 4S 4通过p53依赖性途径诱导胃癌细胞凋亡，具有较强的细胞毒活性。我们的数据表明，As 4S 4可能具有治疗胃癌的潜力。
Background Arsenic sulfide (As4S4), the main component of realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types, especially for acute promyelocytic leukemia. In this study, we aimed to explore the efficacy and mechanism of As4S4 in gastric cancer. Methods The effect of As4S4 on cell proliferation and apoptosis of gastric cancer cells was investigated by MTT assay, 4′,6-diamidino-2-phenylindole (DAPI) staining, and annexin V–fluorescein isothiocyanate/propidium iodide staining using gastric cancer cell lines AGS (harboring wild-type p53) and MGC803 (harboring mutant p53) in vitro. The expression of apoptosis-related proteins was measured by Western blotting, real-time polymerase chain reaction, and immunohistochemistry analysis. Mouse xenograft models were established by inoculation with MGC803 cells, and the morphology and the proportion of apoptotic cells in tumor tissues were detected by hematoxylin and eosin staining and TdT-mediated dUTP nick end labeling (TUNEL) assay, respectively. Results As4S4 inhibited the proliferation and induced apoptosis of AGS and MGC803 cells in a time- and dose-dependent manner. As4S4 upregulated the expression of Bax and MDM2 while downregulated the expression of Bcl-2. The expression of p53 increased significantly in the AGS cells but did not readily increase in the MGC803 cells, which harbored mutant p53. Pifithrin-α, a p53 inhibitor, blocked the modulation of As4S4 on AGS cells, but not on MGC803 cells. Using xenograft as a model, we showed that As4S4 suppressed tumor growth and induced apoptosis in vivo and that the expression of p53 increased accordingly. Conclusion As4S4 is a potent cytotoxic agent for gastric cancer cells, as it induced apoptosis both in vitro and in vivo through a p53-dependent pathway. Our data indicate that As4S4 may have therapeutic potential in gastric cancer.