美洲大蠊多肽PAP-2对H22荷瘤小鼠的抑瘤作用研究
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摘要
目的:探讨美洲大蠊多肽PAP-2对H22荷瘤小鼠的抑瘤作用。方法:通过小鼠腋窝皮下注射H22肝癌小鼠腹水构建荷瘤小鼠模型。将70只小鼠随机分为模型组(生理盐水)、5-氟尿嘧啶组(阳性药对照,20 mg/kg)以及美洲大蠊提取物的脱脂膏组(200 mg/kg,以提取物量计)、CⅡ-3组(从浸膏中提取的以多肽为主要活性成分的组分,200 mg/kg,以提取物量计)和多肽PAP-2高、中、低剂量组(从CⅡ-3中分离得到,200、100、50 mg/kg,以单体量计),每组10只。5-氟尿嘧啶组小鼠隔天腹腔注射给药1次,其余各组小鼠均每天灌胃给药1次,给药周期均为10 d。给药结束后,观察小鼠瘤块变化并测定其脏器(脾、胸腺、肝)指数,苏木精-伊红染色后观察其瘤组织病理变化,并采用酶联免疫吸附试验法测定其血清中血管内皮生长因子(VEGF)、白细胞介素1β(IL-1β)和IL-4的含量。结果:脱脂膏、CⅡ-3和不同剂量的PAP-2均能不同程度地抑制荷瘤小鼠瘤块的生长并升高其脏器指数,且PAP-2的作用具有一定的量效关系。其中,PAP-2高剂量组的抑瘤率(38.95%)显著高于脱脂膏组和CⅡ-3组(P<0.05),并与5-氟尿嘧啶组(40.87%)接近(P>0.05);PAP-2高剂量组小鼠脾指数、胸腺指数、肝指数较模型组均显著升高(P<0.05),并显著高于CⅡ-3组(P<0.05),且其肝指数显著高于脱脂膏组(P<0.05)。此外,PAP-2还可降低荷瘤小鼠血清中VEGF和IL-4含量、升高其血清中IL-1β含量,其中PAP-2高剂量组与模型组比较差异均有统计学意义(P<0.05);并且PAP-2高剂量组小鼠血清中IL-1β含量显著高于脱脂膏组和CⅡ-3组(P<0.05),IL-4含量显著低于脱脂膏组和CⅡ-3组(P<0.05),但是其血清中VEGF含量显著低于脱脂膏组和CⅡ-3组(P<0.05)。结论:美洲大蠊多肽PAP-2对H22荷瘤小鼠具有一定的抑瘤作用,可升高其脏器指数,降低其血清中VEGF、IL-4含量并升高其血清中IL-1β含量。
OBJECTIVE:To investigate anti-tumor effects of Periplaneta americana polypeptide PAP-2 on H22 tumor-bearing mice. METHODS:The mice tumor-bearing model was established by subcutaneous injection of ascites of H22 hepatocellular carcinoma mice via axilla. 70 mice were randomly divided into model group(normal saline),5-FU group(positive drug control,20 mg/kg),P. americana extract skimmed cream group(200 mg/kg,calculated by extract),CⅡ-3 group(polypeptide isolated from skimmed cream as main active ingredient,200 mg/kg,calculated by extract)and polypeptide PAP-2 high-dose,medium-dose and low-dose groups(isolated from CⅡ-3,200,100,50 mg/kg,calculated by monomer),with 10 mice in each group. The mice in the 5-FU group were given intraperitoneal injection once every other day,while the mice in the other groups were given intragastric administration once a day,the administration cycle was 10 d. After medication,the changes of tumor were observed and the organs(spleen,thymus and liver)index were measured. Histopathological changes of tumor tissue were observed after HE staining. The contents of VEGF,IL-1β and IL-4 in serum were determined by ELISA. RESULTS:Skimmed cream,CⅡ-3 and different doses of PAP-2 could inhibit the growth of tumor in tumor-bearing mice to different extent and increase organ index,and PAP-2 showed a dose-effect relationship. The tumor inhibition rate(38.95%)of PAP-2 high dose group was significantly higher than those of skimmed cream group and CⅡ-3 group(P<0.05),which was close to that(40.87%)of 5-FU group(P>0.05).Spleen index,thymus index and liver index of mice in PAP-2 high dose group were significantly those of model group and CⅡ-3 group(P<0.05);and the liver index of mice in PAP-2 high dose group was significantly higher than that of skimmed cream group(P<0.05). In addition,PAP-2 could decrease the serum contents of VEGF and IL-4,and increased serum content of IL-1β,with high dose group showed significant difference compared with model group(P<0.05);the serum content of IL-1β of mice in PAP-2 high dose group was significantly higher the that of skimmed cream group and CⅡ-3 group(P<0.05),serum contnet of IL-4 in PAP-2 high dose group was significantly lower the that of skimmed cream group and C Ⅱ-3 group(P<0.05),but the serum content in which was significantly lower than that of skimmed cream group and C Ⅱ-3 group(P<0.05). CONCLU-SIONS:P. americana polypeptide PAP-2 it has a certern anti-tumor effects on H22 tumor-bearing mice,and its can increase the index of organs of H22 tumor-bearing mice, decrease the contents of VEGF and IL-4 in serum,increase the content of IL-1β in serum.
OBJECTIVE:To investigate anti-tumor effects of Periplaneta americana polypeptide PAP-2 on H22 tumor-bearing mice. METHODS:The mice tumor-bearing model was established by subcutaneous injection of ascites of H22 hepatocellular carcinoma mice via axilla. 70 mice were randomly divided into model group(normal saline),5-FU group(positive drug control,20 mg/kg),P. americana extract skimmed cream group(200 mg/kg,calculated by extract),CⅡ-3 group(polypeptide isolated from skimmed cream as main active ingredient,200 mg/kg,calculated by extract)and polypeptide PAP-2 high-dose,medium-dose and low-dose groups(isolated from CⅡ-3,200,100,50 mg/kg,calculated by monomer),with 10 mice in each group. The mice in the 5-FU group were given intraperitoneal injection once every other day,while the mice in the other groups were given intragastric administration once a day,the administration cycle was 10 d. After medication,the changes of tumor were observed and the organs(spleen,thymus and liver)index were measured. Histopathological changes of tumor tissue were observed after HE staining. The contents of VEGF,IL-1β and IL-4 in serum were determined by ELISA. RESULTS:Skimmed cream,CⅡ-3 and different doses of PAP-2 could inhibit the growth of tumor in tumor-bearing mice to different extent and increase organ index,and PAP-2 showed a dose-effect relationship. The tumor inhibition rate(38.95%)of PAP-2 high dose group was significantly higher than those of skimmed cream group and CⅡ-3 group(P<0.05),which was close to that(40.87%)of 5-FU group(P>0.05).Spleen index,thymus index and liver index of mice in PAP-2 high dose group were significantly those of model group and CⅡ-3 group(P<0.05);and the liver index of mice in PAP-2 high dose group was significantly higher than that of skimmed cream group(P<0.05). In addition,PAP-2 could decrease the serum contents of VEGF and IL-4,and increased serum content of IL-1β,with high dose group showed significant difference compared with model group(P<0.05);the serum content of IL-1β of mice in PAP-2 high dose group was significantly higher the that of skimmed cream group and CⅡ-3 group(P<0.05),serum contnet of IL-4 in PAP-2 high dose group was significantly lower the that of skimmed cream group and C Ⅱ-3 group(P<0.05),but the serum content in which was significantly lower than that of skimmed cream group and C Ⅱ-3 group(P<0.05). CONCLU-SIONS:P. americana polypeptide PAP-2 it has a certern anti-tumor effects on H22 tumor-bearing mice,and its can increase the index of organs of H22 tumor-bearing mice, decrease the contents of VEGF and IL-4 in serum,increase the content of IL-1β in serum.
引文
[1]NAVEENTA K,KHAKOO SI.Hepatocellular carcinoma:prospects for NK cell immunotherapy[J].HLA,2018,12(2):138-144.
[2]LI HM,ZHANG LS.Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy[J].Oncotarget,2017,8(1):1805-1813.
[3]姚蓉蓉,王艳红.肝细胞肝癌免疫微环境的研究进展[J].中国临床医学,2014,21(4):487-496.
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[5]高洁,沈咏梅,岳碧松.美洲大蠊药理作用及其临床疗效的研究进展[J].中药药理与临床,2018,34(4):203-208.
[6]焦春香,刘光明,周萍.天然药物康复新的研究进展[J].时珍国医国药,2008,19(11):2623-2624.
[7]甘平,张旭强,何旭,等.美洲大蠊醇提物对小鼠急性肝损伤的保护作用[J].现代药物与临床,2011,26(3):123-128.
[8]杜一民,陈鸿珊,李树楠,等.治疗乙型肝炎新药肝龙胶囊的药效学初步研究[J].时珍国医国药,2006,17(8):1369-1371.
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[10]何正春,彭芳,宋丽艳,等.美洲大蠊化学成分及药理作用研究进展[J].中国中药杂志,2007,32(21):2326-2331.
[11]吴少辉,彭芳,高鹏飞,等.膜超滤分离美洲大蠊抗肿瘤活性部位小分子肽的研究[J].安徽农业科学,2012,40(4):2041-2042,2089.
[12]胡艳芬,吕小满,刘光明,等.美洲大蠊提取物对3株人肺癌细胞的体外抑制作用[J].大理学院学报,2009,8(12):1-3.
[13]何旭,普小菲,彭芳,等.美洲大蠊提取物对S180荷瘤小鼠肿瘤抑制作用及免疫功能的影响[J].中国实验方剂学杂志,2012,18(15):179-182.
[14]陈俊雅,耿玲,张旭强,等.美洲大蠊提取物CⅡ-3对H22肝癌小鼠血管生成作用的研究[J].肿瘤学杂志,2012,18(5):274-276.
[15]普小菲,罗亦佳,彭芳,等.美洲大蠊提取物CⅡ-3体内外抗HSV-2实验研究[J].大理学院学报,2014,13(10):5-9.
[16]李洪文,耿玲,刘光明,等.美洲大蠊脱脂膏及其活性炭脱色物体外抗菌活性研究[J].中国实验方剂学杂志,2012,18(11):159-161.
[17]张蕊,袁发璐,李婷,等.美洲大蠊提取物对人肝癌HepG2细胞的作用机制研究[J].中国现代医学杂志,2017,27(12):1-8.
[18]李阳,郝艺照,傅熠俊,等.黄连-干姜药对预防DSS诱导的小鼠结肠炎作用及其机制[J].中国实验方剂学杂志,2017,23(15):154-159.
[19]吴会清.灵芝多糖对S180荷瘤小鼠血清细胞因子水平与脏器指数的影响[J].中国药房,2014,25(35):3273-3275.
[20]赵昌林,王珍,骆敏翔,等.番荔枝单体Bullatacin调节Th1/Th2平衡对小鼠H22肝癌的抑制作用研究[J].肿瘤药学,2016,6(4):266-280.
[21]HCHORS K,EVAN G.Tumor angiogenesis:cause or consequence of cancer[J].Cancer Res,2007.DOI:10.1158/0008-5472.
[22]KIM JW,KOH Y,KIM DW.Clinical implications of VEGF,TGF-β1,and IL-1βin patients with advanced nonsmall cell lung cancer[J].Cancer Res Treat,2013,45(4):325-333.
[23]CHEN LC,WANG LJ,TSANG NM,et al.Tumour inflammasome-derived IL-1βrecruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma[J].EMBO Mol Med,2012,4(12):1276-1293.
[2]LI HM,ZHANG LS.Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy[J].Oncotarget,2017,8(1):1805-1813.
[3]姚蓉蓉,王艳红.肝细胞肝癌免疫微环境的研究进展[J].中国临床医学,2014,21(4):487-496.
[4]BISSELL MJ,HINES WC.Why don’t we get more cancer a proposed role of the microenvironment in restraining cancer progression[J].Nat Med,2011,17(3):320-329.
[5]高洁,沈咏梅,岳碧松.美洲大蠊药理作用及其临床疗效的研究进展[J].中药药理与临床,2018,34(4):203-208.
[6]焦春香,刘光明,周萍.天然药物康复新的研究进展[J].时珍国医国药,2008,19(11):2623-2624.
[7]甘平,张旭强,何旭,等.美洲大蠊醇提物对小鼠急性肝损伤的保护作用[J].现代药物与临床,2011,26(3):123-128.
[8]杜一民,陈鸿珊,李树楠,等.治疗乙型肝炎新药肝龙胶囊的药效学初步研究[J].时珍国医国药,2006,17(8):1369-1371.
[9]李武,段丽芳,何贵清,等.美洲大蠊提取物对实验性肝纤维化的影响[J].时珍国医国药,2010,21(5):1137-1138.
[10]何正春,彭芳,宋丽艳,等.美洲大蠊化学成分及药理作用研究进展[J].中国中药杂志,2007,32(21):2326-2331.
[11]吴少辉,彭芳,高鹏飞,等.膜超滤分离美洲大蠊抗肿瘤活性部位小分子肽的研究[J].安徽农业科学,2012,40(4):2041-2042,2089.
[12]胡艳芬,吕小满,刘光明,等.美洲大蠊提取物对3株人肺癌细胞的体外抑制作用[J].大理学院学报,2009,8(12):1-3.
[13]何旭,普小菲,彭芳,等.美洲大蠊提取物对S180荷瘤小鼠肿瘤抑制作用及免疫功能的影响[J].中国实验方剂学杂志,2012,18(15):179-182.
[14]陈俊雅,耿玲,张旭强,等.美洲大蠊提取物CⅡ-3对H22肝癌小鼠血管生成作用的研究[J].肿瘤学杂志,2012,18(5):274-276.
[15]普小菲,罗亦佳,彭芳,等.美洲大蠊提取物CⅡ-3体内外抗HSV-2实验研究[J].大理学院学报,2014,13(10):5-9.
[16]李洪文,耿玲,刘光明,等.美洲大蠊脱脂膏及其活性炭脱色物体外抗菌活性研究[J].中国实验方剂学杂志,2012,18(11):159-161.
[17]张蕊,袁发璐,李婷,等.美洲大蠊提取物对人肝癌HepG2细胞的作用机制研究[J].中国现代医学杂志,2017,27(12):1-8.
[18]李阳,郝艺照,傅熠俊,等.黄连-干姜药对预防DSS诱导的小鼠结肠炎作用及其机制[J].中国实验方剂学杂志,2017,23(15):154-159.
[19]吴会清.灵芝多糖对S180荷瘤小鼠血清细胞因子水平与脏器指数的影响[J].中国药房,2014,25(35):3273-3275.
[20]赵昌林,王珍,骆敏翔,等.番荔枝单体Bullatacin调节Th1/Th2平衡对小鼠H22肝癌的抑制作用研究[J].肿瘤药学,2016,6(4):266-280.
[21]HCHORS K,EVAN G.Tumor angiogenesis:cause or consequence of cancer[J].Cancer Res,2007.DOI:10.1158/0008-5472.
[22]KIM JW,KOH Y,KIM DW.Clinical implications of VEGF,TGF-β1,and IL-1βin patients with advanced nonsmall cell lung cancer[J].Cancer Res Treat,2013,45(4):325-333.
[23]CHEN LC,WANG LJ,TSANG NM,et al.Tumour inflammasome-derived IL-1βrecruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma[J].EMBO Mol Med,2012,4(12):1276-1293.
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