华蟾毒配基抗肿瘤作用研究及安全性评价
摘要
蟾酥为蟾蜍科动物中华大蟾蜍或黑眶蟾蜍的皮肤腺分泌的白色浆液,作为传统中药具有强心、抗心律不齐和升压等作用。目前,蟾酥的抗肿瘤作用成为研究的热点。本论文主要研究蟾酥的活性成分华蟾毒配基对人胃癌BGC-823细胞株增殖和凋亡的影响,并初步探讨其作用机制。
本研究采用不同组织来源的六种肿瘤细胞株：人胃癌细胞株(BGC-823和SGC-7901)、人宫颈癌细胞株(HeLa)、人乳腺癌细胞株(MCF-7)、人肝癌细胞株(SMMC-7721)和人急性早幼粒白血病细胞(HL-60)作为体外细胞模型,检测了华蟾毒配基对其增殖抑制活性,MTT结果显示华蟾毒配基对上述六种细胞株均具有显著增殖抑制作用,且具有时间、剂量依赖性。但对不同组织来源的细胞其抑制强度不同,其中华蟾毒配基对BGC-823细胞最为敏感,半数抑制浓度为0.095μM。
通过Hoechst 33258染色观察和流式细胞仪检测sub-G1凋亡峰发现,华蟾毒配基可以有效诱导BGC-823细胞凋亡性死亡；同时发现华蟾毒配基诱导的细胞凋亡与上调NF-κB的表达有关,通过NF-κB抑制剂PDTC的加入证实了这一点。
我们采用全细胞膜片钳技术检测了华蟾毒配基对BGC-823细胞离子通道电流的影响,结果显示华蟾毒配基可以抑制BGC-823细胞钾离子通道电流,0.05μM和0.25μM的华蟾毒配基使钾离子通道电流分别降低到对照组的82.7±2.9%和51.3±1.7%。
此外,我们进行了华蟾毒配基在小鼠体内的安全性评价,通过morris水迷宫实验和HE组织化学染色,结果显示高浓度的华蟾毒配基(>1.5 mg/kg)具有认知功能损伤和心肌毒性。
以上研究结果表明,华蟾毒配基能够有效诱导BGC-823细胞凋亡,其作用机制可能与NF-κB信号通路有关,为华蟾毒配基在抗肿瘤中的应用奠定了基础。
Chansu which is a traditional Chinese medicine product of the skin secretions of local toads such as Bufo bufo gargarzians Cantor or Bufo bufo melanostictus Schneider, possesses a wide range of biological and pharmacological activity including cardiotonic, anti-arrhythmia and blood pressure stimulation. Recently, the effects of Chansu in tumor cells have been focused on. This study aimed to examin the effects of cinobufagin, the steroid compound isolated from chansu, on proliferation and apoptosis in human gastric cancer BGC-823 cells, and to explore its potential action mechanism.
The results from MTT assay showed that cinobufagin could inhibits the growth of six human tumor cells (human gastric cancer BGC-823 and SGC-7901 cell lines, human hepatoma cell line SMMC-7721, human breast cancer cell line MCF-7, human cervical carcinoma cell line He La, and human promyelocytic leukemia cell line HL-60) in a time and dose-dependent manner. Among the cancer cell lines tested, BGC-823 cells were the most vulnerable to cinobufagin with an IC50 value of approximately 0.095μM.
Results from Hoechst 33258 staining and sub-G1 DNA measurement showed cinobufagin could induce apoptosis in BGC-823 cells. Cinobufagin could increase the expression of NF-κB significantly. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, could suppress the induction of apoptosis and activation of NF-κB in BGC-823 cells by cinobufagin.
Results from whole-cell patch-clamp recording showed that potassium current in BGC-823 was inhibited by cinobufagin in a voltage-dependent manner and percent inhibitions for the blocking action of cinobufagin (0.05μM and 0.25μM) on Ik was 82.7±2.9%and 51.3±1.7%, respectively.
To evaluate the safety of cinobufagin, mice were given to two doses of cinobufagin by intraperitoneal injection. After 30 days injection, organs were examined for damages. Results from water maze showed that cinobufagin (>1.5 mg/kg) could be damage on rats'memory. And histological analysis of cinobufagin treated mice showed that cardiac muscle was the target organ of this toxin.
These results suggest that cinobufagin has the ability to induce apoptosis in BGC-823 cells via to NF-κB activation. The present study might provide scientific foundation for cinobufagin to be exploited to be an agent for tumor.
本研究采用不同组织来源的六种肿瘤细胞株：人胃癌细胞株(BGC-823和SGC-7901)、人宫颈癌细胞株(HeLa)、人乳腺癌细胞株(MCF-7)、人肝癌细胞株(SMMC-7721)和人急性早幼粒白血病细胞(HL-60)作为体外细胞模型,检测了华蟾毒配基对其增殖抑制活性,MTT结果显示华蟾毒配基对上述六种细胞株均具有显著增殖抑制作用,且具有时间、剂量依赖性。但对不同组织来源的细胞其抑制强度不同,其中华蟾毒配基对BGC-823细胞最为敏感,半数抑制浓度为0.095μM。
通过Hoechst 33258染色观察和流式细胞仪检测sub-G1凋亡峰发现,华蟾毒配基可以有效诱导BGC-823细胞凋亡性死亡；同时发现华蟾毒配基诱导的细胞凋亡与上调NF-κB的表达有关,通过NF-κB抑制剂PDTC的加入证实了这一点。
我们采用全细胞膜片钳技术检测了华蟾毒配基对BGC-823细胞离子通道电流的影响,结果显示华蟾毒配基可以抑制BGC-823细胞钾离子通道电流,0.05μM和0.25μM的华蟾毒配基使钾离子通道电流分别降低到对照组的82.7±2.9%和51.3±1.7%。
此外,我们进行了华蟾毒配基在小鼠体内的安全性评价,通过morris水迷宫实验和HE组织化学染色,结果显示高浓度的华蟾毒配基(>1.5 mg/kg)具有认知功能损伤和心肌毒性。
以上研究结果表明,华蟾毒配基能够有效诱导BGC-823细胞凋亡,其作用机制可能与NF-κB信号通路有关,为华蟾毒配基在抗肿瘤中的应用奠定了基础。
Chansu which is a traditional Chinese medicine product of the skin secretions of local toads such as Bufo bufo gargarzians Cantor or Bufo bufo melanostictus Schneider, possesses a wide range of biological and pharmacological activity including cardiotonic, anti-arrhythmia and blood pressure stimulation. Recently, the effects of Chansu in tumor cells have been focused on. This study aimed to examin the effects of cinobufagin, the steroid compound isolated from chansu, on proliferation and apoptosis in human gastric cancer BGC-823 cells, and to explore its potential action mechanism.
The results from MTT assay showed that cinobufagin could inhibits the growth of six human tumor cells (human gastric cancer BGC-823 and SGC-7901 cell lines, human hepatoma cell line SMMC-7721, human breast cancer cell line MCF-7, human cervical carcinoma cell line He La, and human promyelocytic leukemia cell line HL-60) in a time and dose-dependent manner. Among the cancer cell lines tested, BGC-823 cells were the most vulnerable to cinobufagin with an IC50 value of approximately 0.095μM.
Results from Hoechst 33258 staining and sub-G1 DNA measurement showed cinobufagin could induce apoptosis in BGC-823 cells. Cinobufagin could increase the expression of NF-κB significantly. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, could suppress the induction of apoptosis and activation of NF-κB in BGC-823 cells by cinobufagin.
Results from whole-cell patch-clamp recording showed that potassium current in BGC-823 was inhibited by cinobufagin in a voltage-dependent manner and percent inhibitions for the blocking action of cinobufagin (0.05μM and 0.25μM) on Ik was 82.7±2.9%and 51.3±1.7%, respectively.
To evaluate the safety of cinobufagin, mice were given to two doses of cinobufagin by intraperitoneal injection. After 30 days injection, organs were examined for damages. Results from water maze showed that cinobufagin (>1.5 mg/kg) could be damage on rats'memory. And histological analysis of cinobufagin treated mice showed that cardiac muscle was the target organ of this toxin.
These results suggest that cinobufagin has the ability to induce apoptosis in BGC-823 cells via to NF-κB activation. The present study might provide scientific foundation for cinobufagin to be exploited to be an agent for tumor.
引文
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