从中医“阴阳”论探索癌痛消方及其拆方治疗原发性肝癌疗效机制的实验研究
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摘要
目的1.通过检测细胞凋亡率和细胞周期的变化,了解癌痛消方及其拆方治疗原发性肝癌的疗效,并明确癌痛消方中三大类药物君臣配伍地位;
2.研究癌痛消方中三大类药物治疗原发性肝癌的疗效机制；
3.研究传统中医汤方癌痛消治疗原发性肝癌的疗效机制。
方法Wistar雄性大鼠67只,随机选取12只为正常饲养组,普通饲料喂养,供实验结束时取肝脏组织作空白对照用；余55只进行移植性肝癌造模,于造模后第8天随机抽取7只(正常鼠2只,模型鼠5只)验证造模成功后,按比例随机分为5组,癌痛消全方组、理气活血(拆方I)组、清热解毒(拆方II)组、扶正培元(拆方III)组和模型组,每组10只。分别给予相应浓度的药液(均以人体等效剂量按10ml·kg·d-1灌胃,模型组和正常对照组给予相同体积的蒸馏水灌胃,每日2次,连续给药14d。实验结束停药24小时,心脏采血检测血液流变学改变；处死大鼠,行流式细胞仪Antlexin-v/PI叹染色法检测肝癌细胞凋亡率以及细胞周期；RT-PCR.免疫组织化学法检测肝癌组织/正常肝组织Bcl-2、Survivin、Fas、FasL、Caspase-3mRNA和蛋白的表达情况,并通过免疫组织化学法检测肝癌组织中VEGF的蛋白表达。
结果1.癌痛消全方组和清热解毒组的凋亡率均接近于正常组,组间差异均无统计学意义(P>0.05)；活血化瘀组与扶正培元组的凋亡率明显低于正常组,组间差异均有显著性(P<0.05)。在细胞周期的影响方面,癌痛消全方组和清热解毒组大部分肝癌细胞均停留在静止期(GO期)或G1期,极少数肝癌细胞进入到了S期。活血化瘀组与扶正培元组两组中相当大一部分肝癌细胞进入到S期和G2期。
2.在血液流变学多项指标如全血黏度、血浆黏度、红细胞压积、血沉方程K值的测试结果经方差分析,差异均有统计学意义(P<0.01或P<0.05)。癌痛消全方组中各项指标数均低于模型组,差异均具有统计学意义(P<0.01或P<0.05)；各拆方中,活血化瘀组与癌痛消全方组接近,组间差异无统计学意义(P>0.05)。而清热解毒组和扶正培元组两组中各项指数均与模型组相近,两两比较差异无显著性(P>0.05)。癌痛消全方组和活血化瘀组MVD值均明显低于模型组,与模型组两两比较差异均有极显著性(P<0.01),且以上两组组间差异无统计学意义(P>0.05)；清热解毒组与扶正培元组的MVD值与模型组两两比较,差异均无显著性(P>0.05)
3.癌痛消方可明显抑制肝癌细胞中Bcl-2、Survivin mRNA和蛋白的表达。在拆方组中,以清热解毒组疗效最为显著,对Bcl-2、Survivin mRNA及蛋白的影响与癌痛消方接近,组间差异无统计学意义(P>0.05);扶正培元组对Bcl-2mRNA及蛋白无明显影响(P>0.05)；而活血化瘀组可显著上调Bcl-2、Survivin mRNA和蛋白的表达(P<0.01或P<0.05)。Fas、FasL mRNA和蛋白在癌痛消全方组中表达最高,组间差异极显著(P<0.01)；在清热解毒组中同样高表达(P<0.05)；在活血化瘀组中的表达无明显影响(P>0.05)。在扶正培元组中除开Fas mRNA高表达(P<0.05), Fas、FasL蛋白和FasLmRNA的表达均无明显改变(P>0.05)。Caspase-3mRNA和蛋白在癌痛消方组中表达最高；在清热解毒组中同样高表达,且与全方组比较差异无显著性(P>0.05); Caspase-3mRNA在活血化瘀组(拆方I)与扶正培元组(拆方III)中均高表达(P<0.05),但Caspase-3蛋白在两组的表达与模型组组间差异也无显著性(P>0.05)
结论1、癌痛消方中清热解毒药物在促进肝癌细胞凋亡和抑制肝癌细胞增殖等疗效最为显著,从短期疗效来看,该方中清热解毒药物的功用几乎等同于全方,因此作为君药,在肝癌治疗中起主要的治疗作用。
2、癌痛消方中唯有活血化瘀药物可影响肝癌荷瘤机体血液流变学,改善微循环,从而减少癌栓的形成,提高剪切力,能一定程度上抑制肝癌细胞的生长和转移,充分肯定了活血化瘀药物在肝癌治疗中的必要性；同时,活血化瘀药物还能够显著降低MVD,有效抑制肿瘤新生血管形成。因此,我们有理由相信活血化瘀药物在癌痛消方中起到改善肿瘤微环境的作用,通过对抗阴邪(痰瘀)起作用,改变肿瘤生存环境,从而抑制肿瘤的生长和转移。
3、癌痛消方能够显著影响肝癌细胞细胞凋亡信号传导调控因子下调细胞凋亡抑制基因Bcl-2、survivin的表达；以及上调细胞凋亡促进因子Fas、FasL、Caspase-3的表达。其方中清热解毒药物作用最为显著,其次是扶正培元药物；而活血化瘀药物对细胞凋亡信号传导调控因子的表达无明显影响。因此,我们认为癌痛消方中的清热解毒药物发挥着对抗阳邪(恶气)的作用,通过调整细胞凋亡信号的传递,从而促进肝癌细胞凋亡、抑制肝癌细胞增殖。
4、癌痛消方能够从阴阳两个方面作用于肝癌,即可以通过改善血液流变学、抑制肿瘤血管增生等；同时,还能够影响细胞凋亡信号传导调控因子,表现为下调细胞凋亡抑制基因Bcl-2、survivin的表达；以及上调细胞凋亡促进因子Fas、FasL、Caspase-3的表达,从而到达抗肝癌疗效。
Objective:1. Through the detection of apoptosis and cell cycle changes, learn the effect of Aitongxiao Prescription and its split minor prescriptions on primary liver cancer (PLC.), and to explicit the status of the three class of drugs in Aitongxiao Prescription;
2. To study the mechanisms of three class of drugs in Aitongxiao Prescription on primary liver cancer
3. To study the mechanisms of Aitongxiao Prescription on primary liver cancer。
Methods:10male Wistar rats from67s, randomly selected for the normal diet group, fed with normal diet, the liver tissue as control group for the end of the experiment; The remaining57rats were transplanted hepatocellular carcinoma model,eight days after the modeling and randomly selected seven (2normal rats,5models) to verify the success of modeling. Then the50model rats were randomly divided into four groups, namely, the ATXP group, the Blood Circulation (split Prescription I) group, the Detoxification (split Prescription II) group, the Pei-Yuan (split PrescriptionⅢ) group, which all were given the corresponding concentration of the liquid (both human equivalent dose by10ml of·kg·d-1orally, the Model group and Normal Control group was given the same volume of distilled water, twice daily, continuous administration of14d.24hours withdrawal at the end of the experiment, cardiac blood sampling to test Hemorheology; and rats were killed, the line flow cytometry Antlexin-v/PI double staining method were used to detect circulating hepatocellular apoptosis rate and cell cycle; by RT-PCR, immunohistochemistrychemical assay HCC tissue/normal liver of Bcl-2, survivin, Fas, FasL and Caspase-3mRNA and protein expression detected by immunohistochemical staining of VEGF in HCC tissue protein.
Results:1. The apoptosis rates of The ATXP group and Detoxification group was close to the normal group, the difference between the two groups were not statistically significant (P>0.05); but, The apoptosis rates of the Blood Circulation group and Pei-Yuan group were significantly lower than the Normal Control group, the difference between the groups were significant (P<0.05). In the impact of the cell cycle, the majority of liver cancer cells of The ATXP group and Detoxification group remain in the stationary phase (GO phase) or G1phase, just a very small number of liver cancer cells into S phase. While a large portion of liver cancer cells in the Blood Circulation group and Pei-Yuan group into S phase and G2phase.
2. The differences of test results of the whole blood viscosity, plasma viscosity, hematocrit, erythrocyte sedimentation equation K value of hemorheology in all groups by analysis of variance, were statistically significant (P<0.01or P<0.05). The ATXP group was lower than the model group in all these indicators, the differences between two groups were statistically significant (P<0.01or P<0.05); In the split minor prescriptions, the Blood Circulation group approach to The ATXP group, no significant difference between the groups (P>0.05). While the Detoxification group and Pei-Yuan group in the index are similar to the model group, no significant differences among three groups (P>0.05). The MVD value of the ATXP group and Blood Circulation group which hadn't no significant difference between them (P>0.05) were significantly lower than the model group, the differences of pairwise comparisons were highly significant (P<0.01). In addition, the Detoxification group, Pei-Yuan group and model group pairwise comparison, the differences of MVD vale were no differencestatistically significant (P>0.05).
3. The ATXP group can significantly inhibit the expression of Bcl-2, Survivin mRNA and protein in primary liver cancer cells. In the split minor prescriptions, the efficacy of the Detoxification group is most significantly, in which the effect on the expression of Bcl-2, Survivin mRNA and protein is close to the ATXP group, the difference between the groups was not statistically significant (P>0.05); but, the Pei-Yuan group had no significant effect on it (P>0.05); It is worth noting that the Bood Circulation group can significantly Upregulate the expression of Bcl-2, Survivin mRNA and protein (P<0.01or P<0.05).
Fas and FasL mRNA and protein highestly expressed in the ATXP group, the differences of all the groups were extremely significantly (P<0.01); these mRNA and protein also highly expression in the Detoxification group (P<0.05); but no significant effect on the expression in the Blood Circulation group (P>0.05).It should be noted that in the Pei-Yuan group, the expression of Fas and FasL protein and FasL mRNA were no significant changes (P>0.05), but Fas mRNA was high expression (P <0.05). In all groups, caspase-3mRNA and protein highestly expressed in the ATXP group, as same, it also highly expressed in the Detoxification group, compared with the two goups, the difference was not significant (P>0.05). In addition, Caspase-3mRNA are highly expressed in the Blood Circulation group and Pei-Yuan group (P<0.05), but Caspase-3protein in the difference between the expression of the two groups with the model group group no significant (P>0.05).
Conclusions:1. TCM Herb for clearing heat and detoxicating of ATXP can obviously promote apoptosis and inhibit proliferation of hepatoma cells, compared with the other groups, the efficacy of it is the most significant. From short-term efficacy to evaluate the function of TCM Herb for clearing heat and detoxicating is almost equivalent to the whole ATXP, so it plays a major therapeutic role in the treatment of Primary Liver Cancer
2. The blood circulation herb of ATXP is the olny one which can affect blood rheology of tumor-bearing body, improving the Microcirculation to reduce the formation of tumor thrombus, to improve the shear force, therefore, it can inhibit the growth and metastasis of PLC. It is fully affirmed that the blood circulation herb is necessity in the treatment of PLC. Meanwhile, the Blood Circulation drugs can also significantly reduce the MVD value to effectively inhibit tumor angiogenesis. Therefore, we suggest that the blood circulation herb of ATXP fight against Yin pathogen (plegm and blood stasis), to inhibit tumor growth and metastasis by changing tumor survival environment.
3. The ATXP can significantly affect the apoptotic signal transduction regulatory factors in PLC, the performance is down-regulating the apoptosis suppressor genes Bcl-2and survivin expression; at the same time, it can up-regulated the expression of apoptosis promoting factor, such as Fas, FasL and caspase-3, in which the effect of TCM Herb for clearing heat and detoxicating is most significant, followed by the tonic Herb; but the blood circulation drugs of ATXP had no significant effect on the expression of the apoptosis signal transduction regulatory factors. Therefore, we suggest that TCM Herb for clearing heat and detoxicating of ATXP fight against Yang pathogen (Un-Vital Qi) to adjust the transmission of the apoptotic signal, thereby promoting apoptosis and inhibiting proliferation of hepatoma cells. the blood circulation herb of ATXP fight against Yin pathogen, to inhibit tumor growth and metastasis by changing tumor survival environment.
4. The ATXP can fight against PLC from two aspects of Yin and Yang, which can improve blood rheology, and inhibit tumor vascular proliferation; the same time, can also affect the apoptotic signal transduction regulatory factors, the performance is down-regulating the apoptosis suppressor genes Bcl-2and survivin expression; in additon, it can up-regulated the expression of apoptosis promoting factor, such as Fas, FasL and caspase-3, thus play the role of anti-tumor.
2.研究癌痛消方中三大类药物治疗原发性肝癌的疗效机制；
3.研究传统中医汤方癌痛消治疗原发性肝癌的疗效机制。
方法Wistar雄性大鼠67只,随机选取12只为正常饲养组,普通饲料喂养,供实验结束时取肝脏组织作空白对照用；余55只进行移植性肝癌造模,于造模后第8天随机抽取7只(正常鼠2只,模型鼠5只)验证造模成功后,按比例随机分为5组,癌痛消全方组、理气活血(拆方I)组、清热解毒(拆方II)组、扶正培元(拆方III)组和模型组,每组10只。分别给予相应浓度的药液(均以人体等效剂量按10ml·kg·d-1灌胃,模型组和正常对照组给予相同体积的蒸馏水灌胃,每日2次,连续给药14d。实验结束停药24小时,心脏采血检测血液流变学改变；处死大鼠,行流式细胞仪Antlexin-v/PI叹染色法检测肝癌细胞凋亡率以及细胞周期；RT-PCR.免疫组织化学法检测肝癌组织/正常肝组织Bcl-2、Survivin、Fas、FasL、Caspase-3mRNA和蛋白的表达情况,并通过免疫组织化学法检测肝癌组织中VEGF的蛋白表达。
结果1.癌痛消全方组和清热解毒组的凋亡率均接近于正常组,组间差异均无统计学意义(P>0.05)；活血化瘀组与扶正培元组的凋亡率明显低于正常组,组间差异均有显著性(P<0.05)。在细胞周期的影响方面,癌痛消全方组和清热解毒组大部分肝癌细胞均停留在静止期(GO期)或G1期,极少数肝癌细胞进入到了S期。活血化瘀组与扶正培元组两组中相当大一部分肝癌细胞进入到S期和G2期。
2.在血液流变学多项指标如全血黏度、血浆黏度、红细胞压积、血沉方程K值的测试结果经方差分析,差异均有统计学意义(P<0.01或P<0.05)。癌痛消全方组中各项指标数均低于模型组,差异均具有统计学意义(P<0.01或P<0.05)；各拆方中,活血化瘀组与癌痛消全方组接近,组间差异无统计学意义(P>0.05)。而清热解毒组和扶正培元组两组中各项指数均与模型组相近,两两比较差异无显著性(P>0.05)。癌痛消全方组和活血化瘀组MVD值均明显低于模型组,与模型组两两比较差异均有极显著性(P<0.01),且以上两组组间差异无统计学意义(P>0.05)；清热解毒组与扶正培元组的MVD值与模型组两两比较,差异均无显著性(P>0.05)
3.癌痛消方可明显抑制肝癌细胞中Bcl-2、Survivin mRNA和蛋白的表达。在拆方组中,以清热解毒组疗效最为显著,对Bcl-2、Survivin mRNA及蛋白的影响与癌痛消方接近,组间差异无统计学意义(P>0.05);扶正培元组对Bcl-2mRNA及蛋白无明显影响(P>0.05)；而活血化瘀组可显著上调Bcl-2、Survivin mRNA和蛋白的表达(P<0.01或P<0.05)。Fas、FasL mRNA和蛋白在癌痛消全方组中表达最高,组间差异极显著(P<0.01)；在清热解毒组中同样高表达(P<0.05)；在活血化瘀组中的表达无明显影响(P>0.05)。在扶正培元组中除开Fas mRNA高表达(P<0.05), Fas、FasL蛋白和FasLmRNA的表达均无明显改变(P>0.05)。Caspase-3mRNA和蛋白在癌痛消方组中表达最高；在清热解毒组中同样高表达,且与全方组比较差异无显著性(P>0.05); Caspase-3mRNA在活血化瘀组(拆方I)与扶正培元组(拆方III)中均高表达(P<0.05),但Caspase-3蛋白在两组的表达与模型组组间差异也无显著性(P>0.05)
结论1、癌痛消方中清热解毒药物在促进肝癌细胞凋亡和抑制肝癌细胞增殖等疗效最为显著,从短期疗效来看,该方中清热解毒药物的功用几乎等同于全方,因此作为君药,在肝癌治疗中起主要的治疗作用。
2、癌痛消方中唯有活血化瘀药物可影响肝癌荷瘤机体血液流变学,改善微循环,从而减少癌栓的形成,提高剪切力,能一定程度上抑制肝癌细胞的生长和转移,充分肯定了活血化瘀药物在肝癌治疗中的必要性；同时,活血化瘀药物还能够显著降低MVD,有效抑制肿瘤新生血管形成。因此,我们有理由相信活血化瘀药物在癌痛消方中起到改善肿瘤微环境的作用,通过对抗阴邪(痰瘀)起作用,改变肿瘤生存环境,从而抑制肿瘤的生长和转移。
3、癌痛消方能够显著影响肝癌细胞细胞凋亡信号传导调控因子下调细胞凋亡抑制基因Bcl-2、survivin的表达；以及上调细胞凋亡促进因子Fas、FasL、Caspase-3的表达。其方中清热解毒药物作用最为显著,其次是扶正培元药物；而活血化瘀药物对细胞凋亡信号传导调控因子的表达无明显影响。因此,我们认为癌痛消方中的清热解毒药物发挥着对抗阳邪(恶气)的作用,通过调整细胞凋亡信号的传递,从而促进肝癌细胞凋亡、抑制肝癌细胞增殖。
4、癌痛消方能够从阴阳两个方面作用于肝癌,即可以通过改善血液流变学、抑制肿瘤血管增生等；同时,还能够影响细胞凋亡信号传导调控因子,表现为下调细胞凋亡抑制基因Bcl-2、survivin的表达；以及上调细胞凋亡促进因子Fas、FasL、Caspase-3的表达,从而到达抗肝癌疗效。
Objective:1. Through the detection of apoptosis and cell cycle changes, learn the effect of Aitongxiao Prescription and its split minor prescriptions on primary liver cancer (PLC.), and to explicit the status of the three class of drugs in Aitongxiao Prescription;
2. To study the mechanisms of three class of drugs in Aitongxiao Prescription on primary liver cancer
3. To study the mechanisms of Aitongxiao Prescription on primary liver cancer。
Methods:10male Wistar rats from67s, randomly selected for the normal diet group, fed with normal diet, the liver tissue as control group for the end of the experiment; The remaining57rats were transplanted hepatocellular carcinoma model,eight days after the modeling and randomly selected seven (2normal rats,5models) to verify the success of modeling. Then the50model rats were randomly divided into four groups, namely, the ATXP group, the Blood Circulation (split Prescription I) group, the Detoxification (split Prescription II) group, the Pei-Yuan (split PrescriptionⅢ) group, which all were given the corresponding concentration of the liquid (both human equivalent dose by10ml of·kg·d-1orally, the Model group and Normal Control group was given the same volume of distilled water, twice daily, continuous administration of14d.24hours withdrawal at the end of the experiment, cardiac blood sampling to test Hemorheology; and rats were killed, the line flow cytometry Antlexin-v/PI double staining method were used to detect circulating hepatocellular apoptosis rate and cell cycle; by RT-PCR, immunohistochemistrychemical assay HCC tissue/normal liver of Bcl-2, survivin, Fas, FasL and Caspase-3mRNA and protein expression detected by immunohistochemical staining of VEGF in HCC tissue protein.
Results:1. The apoptosis rates of The ATXP group and Detoxification group was close to the normal group, the difference between the two groups were not statistically significant (P>0.05); but, The apoptosis rates of the Blood Circulation group and Pei-Yuan group were significantly lower than the Normal Control group, the difference between the groups were significant (P<0.05). In the impact of the cell cycle, the majority of liver cancer cells of The ATXP group and Detoxification group remain in the stationary phase (GO phase) or G1phase, just a very small number of liver cancer cells into S phase. While a large portion of liver cancer cells in the Blood Circulation group and Pei-Yuan group into S phase and G2phase.
2. The differences of test results of the whole blood viscosity, plasma viscosity, hematocrit, erythrocyte sedimentation equation K value of hemorheology in all groups by analysis of variance, were statistically significant (P<0.01or P<0.05). The ATXP group was lower than the model group in all these indicators, the differences between two groups were statistically significant (P<0.01or P<0.05); In the split minor prescriptions, the Blood Circulation group approach to The ATXP group, no significant difference between the groups (P>0.05). While the Detoxification group and Pei-Yuan group in the index are similar to the model group, no significant differences among three groups (P>0.05). The MVD value of the ATXP group and Blood Circulation group which hadn't no significant difference between them (P>0.05) were significantly lower than the model group, the differences of pairwise comparisons were highly significant (P<0.01). In addition, the Detoxification group, Pei-Yuan group and model group pairwise comparison, the differences of MVD vale were no differencestatistically significant (P>0.05).
3. The ATXP group can significantly inhibit the expression of Bcl-2, Survivin mRNA and protein in primary liver cancer cells. In the split minor prescriptions, the efficacy of the Detoxification group is most significantly, in which the effect on the expression of Bcl-2, Survivin mRNA and protein is close to the ATXP group, the difference between the groups was not statistically significant (P>0.05); but, the Pei-Yuan group had no significant effect on it (P>0.05); It is worth noting that the Bood Circulation group can significantly Upregulate the expression of Bcl-2, Survivin mRNA and protein (P<0.01or P<0.05).
Fas and FasL mRNA and protein highestly expressed in the ATXP group, the differences of all the groups were extremely significantly (P<0.01); these mRNA and protein also highly expression in the Detoxification group (P<0.05); but no significant effect on the expression in the Blood Circulation group (P>0.05).It should be noted that in the Pei-Yuan group, the expression of Fas and FasL protein and FasL mRNA were no significant changes (P>0.05), but Fas mRNA was high expression (P <0.05). In all groups, caspase-3mRNA and protein highestly expressed in the ATXP group, as same, it also highly expressed in the Detoxification group, compared with the two goups, the difference was not significant (P>0.05). In addition, Caspase-3mRNA are highly expressed in the Blood Circulation group and Pei-Yuan group (P<0.05), but Caspase-3protein in the difference between the expression of the two groups with the model group group no significant (P>0.05).
Conclusions:1. TCM Herb for clearing heat and detoxicating of ATXP can obviously promote apoptosis and inhibit proliferation of hepatoma cells, compared with the other groups, the efficacy of it is the most significant. From short-term efficacy to evaluate the function of TCM Herb for clearing heat and detoxicating is almost equivalent to the whole ATXP, so it plays a major therapeutic role in the treatment of Primary Liver Cancer
2. The blood circulation herb of ATXP is the olny one which can affect blood rheology of tumor-bearing body, improving the Microcirculation to reduce the formation of tumor thrombus, to improve the shear force, therefore, it can inhibit the growth and metastasis of PLC. It is fully affirmed that the blood circulation herb is necessity in the treatment of PLC. Meanwhile, the Blood Circulation drugs can also significantly reduce the MVD value to effectively inhibit tumor angiogenesis. Therefore, we suggest that the blood circulation herb of ATXP fight against Yin pathogen (plegm and blood stasis), to inhibit tumor growth and metastasis by changing tumor survival environment.
3. The ATXP can significantly affect the apoptotic signal transduction regulatory factors in PLC, the performance is down-regulating the apoptosis suppressor genes Bcl-2and survivin expression; at the same time, it can up-regulated the expression of apoptosis promoting factor, such as Fas, FasL and caspase-3, in which the effect of TCM Herb for clearing heat and detoxicating is most significant, followed by the tonic Herb; but the blood circulation drugs of ATXP had no significant effect on the expression of the apoptosis signal transduction regulatory factors. Therefore, we suggest that TCM Herb for clearing heat and detoxicating of ATXP fight against Yang pathogen (Un-Vital Qi) to adjust the transmission of the apoptotic signal, thereby promoting apoptosis and inhibiting proliferation of hepatoma cells. the blood circulation herb of ATXP fight against Yin pathogen, to inhibit tumor growth and metastasis by changing tumor survival environment.
4. The ATXP can fight against PLC from two aspects of Yin and Yang, which can improve blood rheology, and inhibit tumor vascular proliferation; the same time, can also affect the apoptotic signal transduction regulatory factors, the performance is down-regulating the apoptosis suppressor genes Bcl-2and survivin expression; in additon, it can up-regulated the expression of apoptosis promoting factor, such as Fas, FasL and caspase-3, thus play the role of anti-tumor.
引文
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