人参皂苷Rg3对人肺腺癌细胞株抗肿瘤作用及相关机制的研究
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摘要
目的：探讨人参皂苷Rg3对人肺腺癌细胞株A549/DDP细胞的抗肿瘤作用,及抑制其侵袭、转移和逆转其耐药的作用,并探讨相关的抑瘤机制。
方法：应用Hoechst33258核染色方法观察Rg3作用后细胞凋亡的形态学改变,采用TUNEL方法检测细胞凋亡情况,采用流式细胞技术检测细胞周期及凋亡情况的改变,应用MTT法检测Rg3对A549/DDP细胞逆转耐药的作用；应用细胞膜流动性实验检测Rg3对A549/DDP细胞膜流动性的改变；应用穿膜实验检测Rg3对A549/DDP细胞侵袭和转移能力的影响；应用Western blotting方法检测Rg3对细胞周期、凋亡相关蛋白及转移、耐药相关蛋白表达的影响。建立人肺腺癌细胞A549/DDP裸鼠移植瘤模型,观察Rg3对肿瘤生长的抑制作用。
结果：Rg3作用后,中、高浓度组可见A549/DDP细胞出现核固缩、核碎裂等典型的凋亡改变；Go/G1期细胞数量明显增加,细胞周期发生阻滞,凋亡率明显增加,与Rg3均呈剂量依赖性;Rg3作用后,A549/DDP细胞对顺铂的耐药性下降,ICso明显降低(P<0.05),耐药指数下降,与对照组比较,细胞膜的流动性明显降低(P<0.05),细胞的穿膜能力明显降低(P<0.05),Rg3作用后,周期蛋白cyclinD1表达明显下降,P21、P27表达明显增加,凋亡蛋白caspase-3、caspase-8表达明显增加,转移相关基因nm23表达明显上调,耐药蛋白LRP的表达无明显改变；Rg3可有效抑制裸鼠移植瘤的生长,Rg3与顺铂联合作用组抑瘤作用最佳。
结论：
1、Rg3具有促进A549/DDP细胞凋亡,抑制其增殖的作用,从而达到抗肿瘤的效果；
2、Rg3具有抑制A549/DDP细胞侵袭、转移的作用；
3、Rg3具有逆转肿瘤细胞化疗耐药的作用；
4、Rg3可能是通过活化了caspase-3、caspase-8的表达诱导细胞发生凋亡而发挥抑瘤作用的；
5、Rg3可能是通过抑制cyclinD1的表达,上调P21、P27表达使细胞周期发生阻滞,抑制细胞增殖；
6、Rg3可通过上调nm23的表达抑制A549/DDP细胞的侵袭和转移能力；
7、Rg3可通过降低细胞膜的流动性达到逆转肿瘤细胞耐药的作用；
8、裸鼠体内实验证实,Rg3具有抑制肿瘤生长的作用,而且与化疗药物联合应用,可以减轻化疗药物的毒副作用,具有增效减毒的功效。
Objective:To explore the anti-tumor effect and mechanisms of 20(R)-ginsenoside Rg3 on human lung adenocarcinoma cell line A549/DDP in vivo and in vitro.
Methods:The apoptosis was analyzed by Hoechst33258 staining method and TUNEL method, and cell cycle was determined by flow cytometry (FCM). MTT was applied to determine the chemosensitivity of A549/DDP to cisplatin. cell membrane lipid fluidity was determined to observe the Rg3 effect to cell chemosensitivity, cell invasion assay was applied to determine the invasion and metastasis change of Rg3 to cell, the protein expression levels of cyclinD1, P21, P27, caspase-3, caspasse-8, nm23, and LRP were determined by Western blotting analyses. The subcutaneous transplantable tumor model of human lung adenocarcinoma in nude mice was established to observe anti-tumor effect of Rg3 in vivo.
Results:The typical apoptosis appearance was induced and the cell cycle was arrested at G0/G1 phase; Rg3 could make the IC50 and drug-resistant index of cisplatin decrease; cell membrane lipid fluidity was decreased; cell invasion ability decreased; anti-tumor effect of Rg3 was dose-dependent; expression of cyclinD1 were down-regulated, P21, P27, caspase-3 and caspase-8 expression was up-regulated; expression of nm23 were upregulated, and LRP expression had no obvious change. In vivo, Rg3 could obviously inhibit the growth of transplanted tumor.
Conclusions:
1、20(R)-ginsenoside Rg3 could inhibit the growth of A549/DDP cells by inhibiting the cells proliferation and promoting apoptosis;
2、The mechanism of apoptosis maybe correlated with up-regulation of caspase-3 and caspase-8;
3、The mechanism of the inhibition of cells proliferation maybe correlated with down-regulation of cyclinD1 and up-regulation of P21 and P27;
4、20(R)-ginsenoside Rg3 can restrain A549/DDP cell invasion and metastasis, and it may have relationship with the upregulation of nm23;
5、20(R)-ginsenoside Rg3 can enhance the A549/DDP cell chemosensitivity to cisplatin, and it may have relationship with the upregulation of caspase-3 and the cell membrane lipid fluidity decreased;
6、In vivo,20(R)-ginsenoside Rg3 associated with chemotherapeutics will present the best anti-tumor effect, and can decrease the toxicity and adverse effect of chemotherapeutics.
方法：应用Hoechst33258核染色方法观察Rg3作用后细胞凋亡的形态学改变,采用TUNEL方法检测细胞凋亡情况,采用流式细胞技术检测细胞周期及凋亡情况的改变,应用MTT法检测Rg3对A549/DDP细胞逆转耐药的作用；应用细胞膜流动性实验检测Rg3对A549/DDP细胞膜流动性的改变；应用穿膜实验检测Rg3对A549/DDP细胞侵袭和转移能力的影响；应用Western blotting方法检测Rg3对细胞周期、凋亡相关蛋白及转移、耐药相关蛋白表达的影响。建立人肺腺癌细胞A549/DDP裸鼠移植瘤模型,观察Rg3对肿瘤生长的抑制作用。
结果：Rg3作用后,中、高浓度组可见A549/DDP细胞出现核固缩、核碎裂等典型的凋亡改变；Go/G1期细胞数量明显增加,细胞周期发生阻滞,凋亡率明显增加,与Rg3均呈剂量依赖性;Rg3作用后,A549/DDP细胞对顺铂的耐药性下降,ICso明显降低(P<0.05),耐药指数下降,与对照组比较,细胞膜的流动性明显降低(P<0.05),细胞的穿膜能力明显降低(P<0.05),Rg3作用后,周期蛋白cyclinD1表达明显下降,P21、P27表达明显增加,凋亡蛋白caspase-3、caspase-8表达明显增加,转移相关基因nm23表达明显上调,耐药蛋白LRP的表达无明显改变；Rg3可有效抑制裸鼠移植瘤的生长,Rg3与顺铂联合作用组抑瘤作用最佳。
结论：
1、Rg3具有促进A549/DDP细胞凋亡,抑制其增殖的作用,从而达到抗肿瘤的效果；
2、Rg3具有抑制A549/DDP细胞侵袭、转移的作用；
3、Rg3具有逆转肿瘤细胞化疗耐药的作用；
4、Rg3可能是通过活化了caspase-3、caspase-8的表达诱导细胞发生凋亡而发挥抑瘤作用的；
5、Rg3可能是通过抑制cyclinD1的表达,上调P21、P27表达使细胞周期发生阻滞,抑制细胞增殖；
6、Rg3可通过上调nm23的表达抑制A549/DDP细胞的侵袭和转移能力；
7、Rg3可通过降低细胞膜的流动性达到逆转肿瘤细胞耐药的作用；
8、裸鼠体内实验证实,Rg3具有抑制肿瘤生长的作用,而且与化疗药物联合应用,可以减轻化疗药物的毒副作用,具有增效减毒的功效。
Objective:To explore the anti-tumor effect and mechanisms of 20(R)-ginsenoside Rg3 on human lung adenocarcinoma cell line A549/DDP in vivo and in vitro.
Methods:The apoptosis was analyzed by Hoechst33258 staining method and TUNEL method, and cell cycle was determined by flow cytometry (FCM). MTT was applied to determine the chemosensitivity of A549/DDP to cisplatin. cell membrane lipid fluidity was determined to observe the Rg3 effect to cell chemosensitivity, cell invasion assay was applied to determine the invasion and metastasis change of Rg3 to cell, the protein expression levels of cyclinD1, P21, P27, caspase-3, caspasse-8, nm23, and LRP were determined by Western blotting analyses. The subcutaneous transplantable tumor model of human lung adenocarcinoma in nude mice was established to observe anti-tumor effect of Rg3 in vivo.
Results:The typical apoptosis appearance was induced and the cell cycle was arrested at G0/G1 phase; Rg3 could make the IC50 and drug-resistant index of cisplatin decrease; cell membrane lipid fluidity was decreased; cell invasion ability decreased; anti-tumor effect of Rg3 was dose-dependent; expression of cyclinD1 were down-regulated, P21, P27, caspase-3 and caspase-8 expression was up-regulated; expression of nm23 were upregulated, and LRP expression had no obvious change. In vivo, Rg3 could obviously inhibit the growth of transplanted tumor.
Conclusions:
1、20(R)-ginsenoside Rg3 could inhibit the growth of A549/DDP cells by inhibiting the cells proliferation and promoting apoptosis;
2、The mechanism of apoptosis maybe correlated with up-regulation of caspase-3 and caspase-8;
3、The mechanism of the inhibition of cells proliferation maybe correlated with down-regulation of cyclinD1 and up-regulation of P21 and P27;
4、20(R)-ginsenoside Rg3 can restrain A549/DDP cell invasion and metastasis, and it may have relationship with the upregulation of nm23;
5、20(R)-ginsenoside Rg3 can enhance the A549/DDP cell chemosensitivity to cisplatin, and it may have relationship with the upregulation of caspase-3 and the cell membrane lipid fluidity decreased;
6、In vivo,20(R)-ginsenoside Rg3 associated with chemotherapeutics will present the best anti-tumor effect, and can decrease the toxicity and adverse effect of chemotherapeutics.
引文
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