组蛋白去乙酰酶抑制剂MS-275选择性抑制SGC-7901细胞生长的实验研究
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摘要
目的：组蛋白去乙酰基化转移酶抑制剂(histone deacetylases inhibitors, HDACis)对于很多肿瘤细胞具有诱导细胞凋亡及分化的作用,而对正常细胞的细胞毒作用很低,这一选择性杀伤作用使HDACis成为目前抗肿瘤分子靶向药物的研究热点,到目前为止已有多种组蛋白去乙酰基化转移酶抑制剂被大量研究,其中的一部分已经进入了临床研究阶段。本文主要研究了HDACis之一MS-275对人胃癌细胞SGC-7901及人胃粘膜正常细胞GES-1和张氏肝细胞(CHANGLIVER)是否具有选择性杀伤作用以及初步探讨这种作用的机制,为HDACis的临床应用提供理论依据。
方法：1.不同终浓度MS-275处理SGC-7901细胞及GES-1和CHANGLIVER细胞,用WST-1方法(细胞增殖实验)检测MS-275对癌细胞和正常细胞的作用,验证MS-275是否对胃癌细胞具有的生长抑制作用但对正常细胞无细胞毒作用；
2. AnnexinV/PI双标流式细胞术检测MS-275对肿瘤细胞SGC-7901和正常细胞的是否发生细胞凋亡；
3. TUNEL染色观察肿瘤细胞核内染色体断裂情况,从而进一步验证MS-275对胃癌细胞的促凋亡作用；
4.通过检测细胞内的DNA含量来研究MS-275干预后胃癌细胞中细胞周期发生的的变化,MS-275是否可以阻滞细胞周期；
5.利用caspase抑制剂的作用来检测caspase对MS-275诱导凋亡的影响,研究MS-275是通过何种途径诱导肿瘤细胞凋亡；
6. West Blot检测MS-275对细胞内Bcl-2蛋白表达水平的影响。
结果：1.MS-275对胃癌细胞SGC-7901具有明显的生长抑制作用,且这种作用具有时间及剂量的依赖性；
2.MS-275的杀伤作用具有选择性,可在胃癌细胞SGC-7901中诱导细胞凋亡,但对正常细胞GES-1和张氏肝细胞CHANGLIVER并不表现出促凋亡作用；
3. TUNEL染色证明MS-275能诱导SGC-7901细胞核内发生DNA断裂,是细胞发生凋亡的重要指标；
4.MS-275能诱导SGC-7901细胞发生Go/G1周期停留,随着药物的处理,可以明显检测到G1期比例增大；
5. caspase抑制剂可以明显抑制MS-275的作用,说明MS-275诱导的细胞凋亡是通过caspase依赖性的途径；
6. Western Blot的结果显示随着MS-275处理时间的增长和处理剂量的增大,凋亡抑制基因bcl-2表达出现下调。
结论：MS-275具有体外选择性杀伤胃癌细胞的作用,对正常细胞没有明显的杀伤作用,不会诱导正常细胞细胞凋亡,MS-275是通过诱导细胞凋亡和周期滞留两方面来发挥作用,并且是通过caspase依赖性的凋亡途径,凋亡抑制基因bcl-2的表达也会发生变化,它有希望成为新一代的胃癌临床治疗的肿瘤分子靶向药物。
AIM:The histone deacetylase inhibitor(HDACi) can selectively induce apoptosis and differentiation on many kinds of tumor cells, but it has no evident cytotoxic effect on normal cells. Because of the specificity, it has become the target as a new anticancer agents and some of them has entered the clinical research phase. This paper aims to investigate the antiproliferation effect and its mechanism of the HDACi MS-275 on inhibiting the gastric cancer cell SGC-7901 and normal cells GES-1 and CHANGLIVER to provide experimental basis for clinical practice.
METHODS:1. Cultured cells SGC-7901, GES-1 and CHANGLIVER were exposed to different concentrations of MS-275 for different durations. The growth inhibition was evaluated by WST-1 assay(cell proliferation assay), to prove that if MS-275 can only induce cell growth arrest on gastric cancer cell but not on normal cell;
2. Cell apoptosis was detected by AnnexinV/PI-labeled flow cytometry;
3. DNA fragmentation in nucleus in SGC-7901 cells can be observed by TUNEL assay, which can testify MS-275 mediated apoptosis from another aspect;
4. Cell cycle status after treated by MS-275 was reflected by the DNA content which was detected by flow cytometry;
5. Use the caspase inhibitor to make out what the role that caspase plays in MS-275-mediated apoptosis and investigate which apoptosis pathway MS-275 involved in;
6. The change of Bcl-2 expression after exposed to MS-275 was detected by Western Blot.
RESULTS:1. MS-275 can inhibit cell growth and induce cell apoptosis in SGC-7901 cell lines in a concentration and time dependent manner, but has no evident effect on normal cells lines;
2. MS-275 can selectively iuduce cell death in SGC-7901 cell but not for GES-1 and CHANGLIVER cells;
3. TUNEL assay proved that MS-275 can induce DNA fragmentation in the nucleus of SGC-7901 cells, which was an important symbol of cell apoptosis;
4. MS-275 can arrest the cell cycle of SGC-7901 at Gl checkpoint, and along with the drug dealing, Gl cells increased obviously;
5. Caspase inhibitor can suppress the apoptosis caused by MS-275, which demonstrated that MS-275 induces caspase-dependent apoptosis;
6. After the exposure to MS-275, Bc1-2 started to downregulates and it turned out to be a concentration and time dependent manner.
CONCLUSION:MS-275 can selectively induce apoptosis in gastric cancer cells in vitro, but not in normal cells; MS-275 can function through inducing apoptosis by caspase-dependent pathway and arresting cell cycle; In addition, MS-275 can also downregulate Bcl-2 which can surpress apoptosis. It would be the new molecular targeted drug for clinical treatment on gastric cancer.
方法：1.不同终浓度MS-275处理SGC-7901细胞及GES-1和CHANGLIVER细胞,用WST-1方法(细胞增殖实验)检测MS-275对癌细胞和正常细胞的作用,验证MS-275是否对胃癌细胞具有的生长抑制作用但对正常细胞无细胞毒作用；
2. AnnexinV/PI双标流式细胞术检测MS-275对肿瘤细胞SGC-7901和正常细胞的是否发生细胞凋亡；
3. TUNEL染色观察肿瘤细胞核内染色体断裂情况,从而进一步验证MS-275对胃癌细胞的促凋亡作用；
4.通过检测细胞内的DNA含量来研究MS-275干预后胃癌细胞中细胞周期发生的的变化,MS-275是否可以阻滞细胞周期；
5.利用caspase抑制剂的作用来检测caspase对MS-275诱导凋亡的影响,研究MS-275是通过何种途径诱导肿瘤细胞凋亡；
6. West Blot检测MS-275对细胞内Bcl-2蛋白表达水平的影响。
结果：1.MS-275对胃癌细胞SGC-7901具有明显的生长抑制作用,且这种作用具有时间及剂量的依赖性；
2.MS-275的杀伤作用具有选择性,可在胃癌细胞SGC-7901中诱导细胞凋亡,但对正常细胞GES-1和张氏肝细胞CHANGLIVER并不表现出促凋亡作用；
3. TUNEL染色证明MS-275能诱导SGC-7901细胞核内发生DNA断裂,是细胞发生凋亡的重要指标；
4.MS-275能诱导SGC-7901细胞发生Go/G1周期停留,随着药物的处理,可以明显检测到G1期比例增大；
5. caspase抑制剂可以明显抑制MS-275的作用,说明MS-275诱导的细胞凋亡是通过caspase依赖性的途径；
6. Western Blot的结果显示随着MS-275处理时间的增长和处理剂量的增大,凋亡抑制基因bcl-2表达出现下调。
结论：MS-275具有体外选择性杀伤胃癌细胞的作用,对正常细胞没有明显的杀伤作用,不会诱导正常细胞细胞凋亡,MS-275是通过诱导细胞凋亡和周期滞留两方面来发挥作用,并且是通过caspase依赖性的凋亡途径,凋亡抑制基因bcl-2的表达也会发生变化,它有希望成为新一代的胃癌临床治疗的肿瘤分子靶向药物。
AIM:The histone deacetylase inhibitor(HDACi) can selectively induce apoptosis and differentiation on many kinds of tumor cells, but it has no evident cytotoxic effect on normal cells. Because of the specificity, it has become the target as a new anticancer agents and some of them has entered the clinical research phase. This paper aims to investigate the antiproliferation effect and its mechanism of the HDACi MS-275 on inhibiting the gastric cancer cell SGC-7901 and normal cells GES-1 and CHANGLIVER to provide experimental basis for clinical practice.
METHODS:1. Cultured cells SGC-7901, GES-1 and CHANGLIVER were exposed to different concentrations of MS-275 for different durations. The growth inhibition was evaluated by WST-1 assay(cell proliferation assay), to prove that if MS-275 can only induce cell growth arrest on gastric cancer cell but not on normal cell;
2. Cell apoptosis was detected by AnnexinV/PI-labeled flow cytometry;
3. DNA fragmentation in nucleus in SGC-7901 cells can be observed by TUNEL assay, which can testify MS-275 mediated apoptosis from another aspect;
4. Cell cycle status after treated by MS-275 was reflected by the DNA content which was detected by flow cytometry;
5. Use the caspase inhibitor to make out what the role that caspase plays in MS-275-mediated apoptosis and investigate which apoptosis pathway MS-275 involved in;
6. The change of Bcl-2 expression after exposed to MS-275 was detected by Western Blot.
RESULTS:1. MS-275 can inhibit cell growth and induce cell apoptosis in SGC-7901 cell lines in a concentration and time dependent manner, but has no evident effect on normal cells lines;
2. MS-275 can selectively iuduce cell death in SGC-7901 cell but not for GES-1 and CHANGLIVER cells;
3. TUNEL assay proved that MS-275 can induce DNA fragmentation in the nucleus of SGC-7901 cells, which was an important symbol of cell apoptosis;
4. MS-275 can arrest the cell cycle of SGC-7901 at Gl checkpoint, and along with the drug dealing, Gl cells increased obviously;
5. Caspase inhibitor can suppress the apoptosis caused by MS-275, which demonstrated that MS-275 induces caspase-dependent apoptosis;
6. After the exposure to MS-275, Bc1-2 started to downregulates and it turned out to be a concentration and time dependent manner.
CONCLUSION:MS-275 can selectively induce apoptosis in gastric cancer cells in vitro, but not in normal cells; MS-275 can function through inducing apoptosis by caspase-dependent pathway and arresting cell cycle; In addition, MS-275 can also downregulate Bcl-2 which can surpress apoptosis. It would be the new molecular targeted drug for clinical treatment on gastric cancer.
引文
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