IP_6对人结肠癌裸鼠皮下移植瘤生长的干预作用研究
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摘要
目的：研究肌醇六磷酸(Inositol Hexaphosphate, IP6)对人结肠癌裸鼠皮下移植瘤生长的影响,并探讨相关生物学机制,为IP6的应用提供依据。
方法：建立人结肠癌裸鼠皮下移植瘤模型,并按移植瘤体积随机区组为4组,每组6只。对照组：生理盐水；5-氟尿嘧啶组(20 mg/kg);IP6干预组：分为低剂量组(40 mg/kg)和高剂量组(100 mg/kg),各组注射剂量均调整至0.5ml,每日腹腔注射一次。用药28d后经颈椎脱位处死小鼠。检测各组裸鼠皮下移植瘤的体积、重量以及裸鼠实验前后体重的变化,并取移植瘤及肝、肾进行病理学检测。应用荧光显微镜及电镜观察各组移植瘤组织及细胞的变化,Hoechst染色及TUNEL法检测移植瘤内细胞凋亡情况,免疫组化、RT-PCR及Western-blot印迹法检测癌细胞内PCNA、P53、bcl-2、及bax表达情况。
结果：24只裸鼠经皮下注射一定浓度人结肠癌HT-29细胞后,全部成瘤,成瘤率100%。实验期间,除5-FU组小鼠状态较差,一只出现死亡外,其余各组小鼠状态良好,未出现任何不良反应。由裸鼠皮下移植瘤生长曲线可见,与对照组相比,IP6干预组、5-FU组裸鼠皮下移植瘤的生长减慢。对照组、低、高IP6剂量组及5-FU组给药前后移植瘤体积的变化分别为(0.66±0.15)cm3、(0.45±0.06)cm3、(0.41±0.08)cm3、(0.26±0.54)cm3,IP6干预组与对照组及5-FU组相比,均存在显著性差异(P＜0.05),IP6干预组间无显著性差异(P＞0.05)；对照组、低、高IP6剂量组及5-FU组瘤重分别为(0.80±0.22)g、(0.50±0.10)g、(0.46±0.13)g、(0.25±0.92)g,与对照组相比,IP6干预组瘤重降低,差别具有显著性(P＜0.05),与5-FU组比,差别也具有显著性(P＜0.05),IP6干预组间无显著性差异(P＞0.05)。Hoechst染色及TUNEL检测结果显示,与对照组相比,IP6干预组癌细胞的凋亡率显著升高(P＜0.05)；免疫组化结果表明,IP6干预组癌细胞内PCNA及突变型P53蛋白的表达降低,与对照组相比,差别具有显著性(P＜0.05)；RT-PCR及Western-blot检测显示,IP6干预组癌细胞内bax表达升高,bcl-2的表达降低,与对照组相比,差别具有统计学意义(P＜O.05)。
结论：IP6可显著抑制人结肠癌裸鼠皮下移植瘤的生长,具有明显的抗癌作用,且IP6发挥抗癌作用时,副作用小,安全性高。IP6能降低癌细胞PCNA及突变型P53的表达,并调节凋亡相关基因bcl-2及bax的表达,影响癌细胞内信号转导,抑制癌细胞增殖,促进癌细胞凋亡。
Objective:To investigate the effect and explore the related mechanism of IP6(Inositol Hexaphosphate, IP6) on the treatment of human colorectal cancer in nude mice subcutaneous xenograft model, for the clinical treatment of colon cancer to provide experimental basis.
Methods:Models of human colorectal cancer xenografts in nude mice were established and divided randomly into four groups. Each group included six mice.Control group:injected normal saline; 5-FU group:injection according to 20 mg/kg; IP6 groups: divided into low-does IP6 group (40mg/kg) and high-does group (100mg/kg); 0.5ml reagent was given to each mouse by intraperitoneal injection once a day. After continuous administration of 28d, the mice were killed by broking necks. During the experiment, we observed the general state of nude mice and detected transplanted tumors'size, weight. After the experiment, tumor, liver and kidney were got to do pathological detection. Fluorescence microscopy and electron microscopy were used to detect the changes of tumor tissues and cells.Hoechst staining and TUNEL were applied to assay apoptosis of tumor cells; the methods of immunohistochemistry, PT-PCR and westem-blot were adopted to detect the expression of PCNA, P53, bcl-2, and bax.
Results:All of 24 models of HT-29 cell xenografts were formed after subcutaneous injection of a certain concentration of human colon cancer HT-29 cells; tumor formation rate was 100%. All of mice were in good condition during the experiment, no adverse reactions occur, except the mice in 5-FU group. Mice in 5-FU group were in poor state, even that one was dead. The growth curve of subcutaneous tumor showed that compared with control group, the growth of subcutaneous tumors in IP6 groups and 5-FU group slowed down. The changes of control group, low-dose IP6 group, high-dose IP6 group and 5-FU group respectively were (0.66±0.15) cm3、(0.45±0.06) cm3、(0.41±0.08) cm3 (0.26±0.54) cm3.There was no significant difference between low-dose IP6 group and high-dose IP6 group. The differences between IP6 groups and control groups were significant (P<0.05).Compared with 5-FUgroup, IP6 groups also had significant differences (P<0.05).Howere, there was no significant difference between low-dose IP6 group and high-dose IP6 group. The tumor weights of control groups,low-dose IP6 group, high-dose IP6 group and 5-FU group respectively were (0.80±0.22) g、(0.50±0.10) g、(0.46±0.13) g、(0.25±0.92) g. Compared with control group, the weight of tumors in IP6 groups and 5-FU group decreased significantly (P<0.05); there was no significant difference (P>0.05) between IP6 groups; the difference between IP6 groups and 5-FU group was significant (P<0.05).Hoechst staining and TUNEL assay showed cell apoptosis increased significantly in IP6 groups (P<0.05), comparing with control group. Immunohistochemistry showed PCNA and P53 protein expression was significantly lower in IP6 groups (P<0.05); RT-PCR and Western-blot showed that compared with the control group, the expression of bax significantly increased (P<0.05), bcl-2 expression significant ly decreased (P<0.05).
Conclusion:IP6 has significant effects to inhibit the growth of tumor. And IP6 has fewer side effects, comparing with 5-FU. IP6 can reduce the expression of PCNA and P53 and regulate the expression of gene bcl-2 and bax, affecting signal transduction within cancer cells to inhibit cancer cell proliferation and promote apoptosis.
方法：建立人结肠癌裸鼠皮下移植瘤模型,并按移植瘤体积随机区组为4组,每组6只。对照组：生理盐水；5-氟尿嘧啶组(20 mg/kg);IP6干预组：分为低剂量组(40 mg/kg)和高剂量组(100 mg/kg),各组注射剂量均调整至0.5ml,每日腹腔注射一次。用药28d后经颈椎脱位处死小鼠。检测各组裸鼠皮下移植瘤的体积、重量以及裸鼠实验前后体重的变化,并取移植瘤及肝、肾进行病理学检测。应用荧光显微镜及电镜观察各组移植瘤组织及细胞的变化,Hoechst染色及TUNEL法检测移植瘤内细胞凋亡情况,免疫组化、RT-PCR及Western-blot印迹法检测癌细胞内PCNA、P53、bcl-2、及bax表达情况。
结果：24只裸鼠经皮下注射一定浓度人结肠癌HT-29细胞后,全部成瘤,成瘤率100%。实验期间,除5-FU组小鼠状态较差,一只出现死亡外,其余各组小鼠状态良好,未出现任何不良反应。由裸鼠皮下移植瘤生长曲线可见,与对照组相比,IP6干预组、5-FU组裸鼠皮下移植瘤的生长减慢。对照组、低、高IP6剂量组及5-FU组给药前后移植瘤体积的变化分别为(0.66±0.15)cm3、(0.45±0.06)cm3、(0.41±0.08)cm3、(0.26±0.54)cm3,IP6干预组与对照组及5-FU组相比,均存在显著性差异(P＜0.05),IP6干预组间无显著性差异(P＞0.05)；对照组、低、高IP6剂量组及5-FU组瘤重分别为(0.80±0.22)g、(0.50±0.10)g、(0.46±0.13)g、(0.25±0.92)g,与对照组相比,IP6干预组瘤重降低,差别具有显著性(P＜0.05),与5-FU组比,差别也具有显著性(P＜0.05),IP6干预组间无显著性差异(P＞0.05)。Hoechst染色及TUNEL检测结果显示,与对照组相比,IP6干预组癌细胞的凋亡率显著升高(P＜0.05)；免疫组化结果表明,IP6干预组癌细胞内PCNA及突变型P53蛋白的表达降低,与对照组相比,差别具有显著性(P＜0.05)；RT-PCR及Western-blot检测显示,IP6干预组癌细胞内bax表达升高,bcl-2的表达降低,与对照组相比,差别具有统计学意义(P＜O.05)。
结论：IP6可显著抑制人结肠癌裸鼠皮下移植瘤的生长,具有明显的抗癌作用,且IP6发挥抗癌作用时,副作用小,安全性高。IP6能降低癌细胞PCNA及突变型P53的表达,并调节凋亡相关基因bcl-2及bax的表达,影响癌细胞内信号转导,抑制癌细胞增殖,促进癌细胞凋亡。
Objective:To investigate the effect and explore the related mechanism of IP6(Inositol Hexaphosphate, IP6) on the treatment of human colorectal cancer in nude mice subcutaneous xenograft model, for the clinical treatment of colon cancer to provide experimental basis.
Methods:Models of human colorectal cancer xenografts in nude mice were established and divided randomly into four groups. Each group included six mice.Control group:injected normal saline; 5-FU group:injection according to 20 mg/kg; IP6 groups: divided into low-does IP6 group (40mg/kg) and high-does group (100mg/kg); 0.5ml reagent was given to each mouse by intraperitoneal injection once a day. After continuous administration of 28d, the mice were killed by broking necks. During the experiment, we observed the general state of nude mice and detected transplanted tumors'size, weight. After the experiment, tumor, liver and kidney were got to do pathological detection. Fluorescence microscopy and electron microscopy were used to detect the changes of tumor tissues and cells.Hoechst staining and TUNEL were applied to assay apoptosis of tumor cells; the methods of immunohistochemistry, PT-PCR and westem-blot were adopted to detect the expression of PCNA, P53, bcl-2, and bax.
Results:All of 24 models of HT-29 cell xenografts were formed after subcutaneous injection of a certain concentration of human colon cancer HT-29 cells; tumor formation rate was 100%. All of mice were in good condition during the experiment, no adverse reactions occur, except the mice in 5-FU group. Mice in 5-FU group were in poor state, even that one was dead. The growth curve of subcutaneous tumor showed that compared with control group, the growth of subcutaneous tumors in IP6 groups and 5-FU group slowed down. The changes of control group, low-dose IP6 group, high-dose IP6 group and 5-FU group respectively were (0.66±0.15) cm3、(0.45±0.06) cm3、(0.41±0.08) cm3 (0.26±0.54) cm3.There was no significant difference between low-dose IP6 group and high-dose IP6 group. The differences between IP6 groups and control groups were significant (P<0.05).Compared with 5-FUgroup, IP6 groups also had significant differences (P<0.05).Howere, there was no significant difference between low-dose IP6 group and high-dose IP6 group. The tumor weights of control groups,low-dose IP6 group, high-dose IP6 group and 5-FU group respectively were (0.80±0.22) g、(0.50±0.10) g、(0.46±0.13) g、(0.25±0.92) g. Compared with control group, the weight of tumors in IP6 groups and 5-FU group decreased significantly (P<0.05); there was no significant difference (P>0.05) between IP6 groups; the difference between IP6 groups and 5-FU group was significant (P<0.05).Hoechst staining and TUNEL assay showed cell apoptosis increased significantly in IP6 groups (P<0.05), comparing with control group. Immunohistochemistry showed PCNA and P53 protein expression was significantly lower in IP6 groups (P<0.05); RT-PCR and Western-blot showed that compared with the control group, the expression of bax significantly increased (P<0.05), bcl-2 expression significant ly decreased (P<0.05).
Conclusion:IP6 has significant effects to inhibit the growth of tumor. And IP6 has fewer side effects, comparing with 5-FU. IP6 can reduce the expression of PCNA and P53 and regulate the expression of gene bcl-2 and bax, affecting signal transduction within cancer cells to inhibit cancer cell proliferation and promote apoptosis.
引文
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