Erufosine对胃癌细胞及骨髓细胞增殖抑制的影响

摘要

背景与目的:PI3K/Akt信号传导通路与肿瘤转化、进展及放化疗抵抗密切相关.因此,此通路是一个潜在的肿瘤靶点.小分子化合物Erufosine为Akt抑制剂,能抑制多种肿瘤细胞生长.本研究观察小分子化合物Erufosine对胃癌细胞和正常骨髓细胞的增殖及对信号传导分子Akt表达的影响,并探讨其对癌细胞的作用机制.方法:使用MTS方法观察胃癌AGS细胞在Erufosine作用下的增殖抑制,计算其IC50及IC90值:在种植胃癌AGS瘤鼠尾静脉内注射Erufosine,定量计数胃癌AGS细胞、人及鼠骨髓细胞的骨髓克隆形成实验(colony forming unit-granulocyte-macrophage,CFU-GM)数,用Western blot法检测Erufosine对AGS瘤细胞Akt表达的影响.结果:Erufosine对胃癌AGS细胞的增殖有明显抑制作用,AGS细胞的IC50和IC90分别为(5.8±2.6)μmol/L和(13.5±4.6) μmol/L；人骨髓细胞的IC50和IC90分别为(96.5±32.6)μ mol/L和(232.8±42.8)μmol/L,鼠骨髓细胞的IC50和IC90分别为(65.5±28.6) μmol/L和(228.8±54.8)μmol/L,与对肿瘤细胞的抑制相比,Erufosine对人和鼠骨髓细胞的毒性较低,两组IC50及IC90的差异均有统计学意义(P＜0.01).人和鼠骨髓细胞的CFU-GM抑制较低,人骨髓细胞的CFU-GM IC50和IC90分别为(86.5±18.6) μmol/L和(250.8±48.8)μmol/L,胃癌AGS细胞的CFU-GM IC50和IC90分别为(7.8±2.5) μmol/L和(13.6±3.6) μmol/L,抑制明显,两者的IC90相差约25倍,两组IC50及IC90的差异均有统计学意义(P＜0.01)； Erufosine抑制胃癌AGS细胞的Akt表达.结论:Erufosine是对胃癌细胞具有明显抑制,且对骨髓有保护作用的新化合物.%Background and purpose: The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is frequently deregulated in cancer and associated with neoplastic transformation, malignant progression, and enhanced resistance to classical chemotherapy and radiotherapy. Thus, it is a promising target for therapeutic intervention. This study aimed to observe the proliferation inhibition of Erufosine on human malignant cells and myeloprotection of healthy bone marrow cells. Methods: Human gastric cancer cell line AGS and human and mouse bone marrow cells were exposed to Erufosine in MTS and CFU-GM assays. CFU-GM of AGS and human and mouse bone marrow cells ex vivo were quantified following intravenous administration of Erufosine to tumor-bearing mice. Western blot method was applied to AGS cells exposed to Erufosine to investigate Akt inhibition. Results: Inhibition of Erufosine proliferation in human and mouse bone marrow cells was less than to gastric cancer AGS cell. The IC50 and IC90 of AGS cells were (5.8±2.6)umol/L and (13.5±4.6)umol/L respectively, the 1C50 and IC90 of human bone marrow cells were (96.5±32.6) umol/L and (232.8±42.8)umol/L respectively; and the IC50 and IC90 of mouse bone marrow cells were (65.5±28.6) Hmol/L and (228.8±54.8)umol/L respectively. There was less cytotoxicity to human and mouse bone marrow cells,compared to the inhibition of tumor cells. Its difference in IC90 was about 20 times. The difference between IC50 and IC90 was statistically significant between the two groups(.P<0.01). More sensitivity to Erufosine exposure in gastric cancer AGS cell was observed compared to bone marrow cells by about twenty-fold differential in IC90 values. There was a statistically significant difference between IC50 and IC90 between the 2 groups (.PO.01). Erufosine injected intravenously significantly reduced AGS tumor cell colony formation ex vivo. Erufosine inhibited Akt expression in AGS cells. Conclusion: Erufosine is a novel compound with a lower toxicity level on bone marrow cells compared to gastric cancer AGS cell which allows for systemic administration.