莪术油对卵巢癌裸鼠移植瘤的抑制作用及其联合顺铂的协同作用研究
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摘要
目的探讨莪术油对卵巢癌裸鼠移植瘤的抑制作用,并探讨其与顺铂联合的协同作用。方法建立卵巢癌细胞株HO-8910PM荷瘤裸鼠模型,随机分为模型对照组、莪术油组、顺铂组和联合给药组(莪术油+顺铂)4组,每组6只,分别腹腔注射莪术油(300 mg·kg-1)、顺铂(2 mg·kg-1)、莪术油联合顺铂(300 mg·kg-1+2 mg·kg-1)以及空白对照液(0.4 mL生理盐水),给药3周后处死小鼠并测瘤体积变化,计算肿瘤生长抑制率,免疫组化检测各组肿瘤组织中NM23、TNF-α、VEGF、NF-KBP65、PCNA的蛋白表达。ELISA检测裸鼠血清中IL-2、IFN-γ水平。结果与模型对照组比较,莪术油、顺铂及其联合给药后均能显著抑制裸鼠肿瘤体积的增长(P<0.05或P<0.01),且联合给药的抑瘤率(55.06%)要高于莪术油(20.5%)和顺铂(52.52%)单独给药。免疫组化检测结果显示各组药物治疗后,能显著降低裸鼠肿瘤组织中NM23、TNF-α、VEGF、NF-KBP65、PCNA的阳性表达(P<0.05或P<0.01),且降低程度从低到高依次为莪术油组、顺铂组、联合给药组。ELISA检测结果也表明顺铂以及莪术油联合顺铂给药3周后能显著提高裸鼠血清IL-2、IFN-γ水平(P<0.01),且含量上升程度由低到高依次为莪术油组、顺铂组、联合给药组。结论莪术油能够抑制卵巢癌荷瘤裸鼠移植瘤的增长,具有一定的抗肿瘤效果,其机制可能与调节肿瘤生长因子NM23、TNF-α、VEGF、NF-KBP65、PCNA及免疫相关因子IL-2、IFN-γ的表达有关。莪术油联合顺铂用药对卵巢癌肿瘤的抑制具有潜在的协同作用,但还需更深入实验研究。
OBJECTIVE To investigate antitumor effect of zedoray turmeric oil(ZTO) on nude mice bearing ovarian cancer and explore its synergistic effect with cisplatin. METHODS After the establishment of HO-8910 PM tumor-bearing mice model, the mice were randomly divided into four groups: model control group(normal saline); ZTO group(300 mg·kg-1);cisplatin group(2 mg·kg-1); combination group(300 mg·kg-1 ZTO+2 mg·kg-1 cisplatin). The nude mice were sacrificed after three weeks of treatment, tumor volume in each group were detected and tumor inhibition rate were calculated. The expression of NM23, TNF-α, VEGF, NF-KBP65, PCNA in tumor tissues were determined by immunohistochemical. ELISA analysis was performed to evaluate the serum level of IL-2 and IFN-γon in nude mice. RESULTS Compared with model group, the tumor volume were significantly decreased in ZTO, cisplatin and combination group(P<0.05 or P<0.01). And the tumor inhibition rates were 20.55%, 52.52%, 55.06%, respectively. Immunohistochemical results showed that the expression of NM23, TNF-α, VEGF,NF-KBP65, PCNA could be significantly decreased with the administration of ZTO, cisplatin, ZTO and cisplatin combined(P<0.05 or P<0.01), and the tendency from low to high were ZTO, cisplatin, ZTO and cisplatin combined in turn. The levels of IL-2 and IFN-γ were also significantly increased with treatment of cisplatin as well as ZTO and cisplatin combined(P<0.01), and the tendency from low to high was the same to above. CONCLUSION ZTO has the anti-tumor effect on ovarian cancer, the underlying mechanism maybe related with regulation of the expression of tumor growth cytokine NM23, TNF-α, VEGF,NF-KBP65, PCNA and immune-related factors IL-2, IFN-γ. And ZTO combined with cisplatin have potential synergistic attenuated the antitumor effect in nude mice of ovarian cancer.
OBJECTIVE To investigate antitumor effect of zedoray turmeric oil(ZTO) on nude mice bearing ovarian cancer and explore its synergistic effect with cisplatin. METHODS After the establishment of HO-8910 PM tumor-bearing mice model, the mice were randomly divided into four groups: model control group(normal saline); ZTO group(300 mg·kg-1);cisplatin group(2 mg·kg-1); combination group(300 mg·kg-1 ZTO+2 mg·kg-1 cisplatin). The nude mice were sacrificed after three weeks of treatment, tumor volume in each group were detected and tumor inhibition rate were calculated. The expression of NM23, TNF-α, VEGF, NF-KBP65, PCNA in tumor tissues were determined by immunohistochemical. ELISA analysis was performed to evaluate the serum level of IL-2 and IFN-γon in nude mice. RESULTS Compared with model group, the tumor volume were significantly decreased in ZTO, cisplatin and combination group(P<0.05 or P<0.01). And the tumor inhibition rates were 20.55%, 52.52%, 55.06%, respectively. Immunohistochemical results showed that the expression of NM23, TNF-α, VEGF,NF-KBP65, PCNA could be significantly decreased with the administration of ZTO, cisplatin, ZTO and cisplatin combined(P<0.05 or P<0.01), and the tendency from low to high were ZTO, cisplatin, ZTO and cisplatin combined in turn. The levels of IL-2 and IFN-γ were also significantly increased with treatment of cisplatin as well as ZTO and cisplatin combined(P<0.01), and the tendency from low to high was the same to above. CONCLUSION ZTO has the anti-tumor effect on ovarian cancer, the underlying mechanism maybe related with regulation of the expression of tumor growth cytokine NM23, TNF-α, VEGF,NF-KBP65, PCNA and immune-related factors IL-2, IFN-γ. And ZTO combined with cisplatin have potential synergistic attenuated the antitumor effect in nude mice of ovarian cancer.
引文
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[14]BAI Y,XIONG Y J,LIU X G.Expressions and significances of mitofusin-2,Survivin and nm23 in ovarian cancer[J].Mater Child Health Care China(中国妇幼保健),2014,29(13):2079-2081.
[15]CHUFFA A,GUSTAVO L,FERREIRA M,et al.P-MAPAimmunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling[J].JOvarian Res,2018(11):8-18.
[16]古月娟.紫杉醇联合顺铂治疗对卵巢癌患者血清中TNF-α、IL-6和E-cadherin水平的影响[J].卫生职业教育,2017(22):153-155.
[17]CHEN G W,ZHOU Y X,ZHANG J Q,et al.Study of the expression of VEGF,estrogen receptor and progesterone receptor in endometrial adenocarc and its clinicalpathologic feature[J].J Pract Obstetrics Gynecol(实用妇产科杂志),2016,32(2):96-99.
[18]邓志鸿.PCNA在肿瘤病理学上的应用[J].临床与实验病理学杂志,1994(4):331-333.
[19]ANTONY G K,DUDEK A Z.Interleukin 2 in cancer therapy[J].Curr Med Chem,2013,17(29):3297-3302.
[20]AQBI H F,WALLACE M,SAPPAL S,et al.IFN-γorchestrates tumor elimination,tumor dormancy,tumor escape,and progression[J].J Leukocyte Biol,2018(103):1219-1223.
[2]ZHANG W.Research survey of Chinese native medicine Ezhu[J].J Guangxi Acad Sci(广西科学院学报),2006,22(z1):481-486.
[3]方刚,肖夏清,韩丽娟,等.莪术油抗肿瘤的临床应用及实验研究进展[J].广西中医药大学学报,2009,12(1):61-63.
[4]李国栋,许付,沈爱军.莪术油的研究进展[J].中国药学杂志,2002,37(11):806-809.
[5]DING H Y,TONG Y H,XIN W X,et al.A literature review on economic evaluation of bevacizumab in treatment of ovarian cancer[J].Chin J Mod Appl Pharm(中国现代应用药学),2017,34(11):1621-1627.
[6]BRAY F,FERLAY J,JEMAL A,et al.Global cancer statistics2018:globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer JClin,2018,68(6):394-424.
[7]LIANG D,YANG M C,LIN Z,et al.The effect of zedoary turmeric oil injection combined with conventional chemotherapy on life quality of the patients with early stage ovarian cancer[J].Chin J Diffic Compl Cas(疑难病杂志),2014,13(5):448-450.
[8]刘竹,韩凤娟,吴效科,等莪术油的抗肿瘤及治疗卵巢癌的研究概况[J].现代中西医结合杂志,2010,19(17):2209-2210.
[9]郭敏红,索玉平,郝美峰,等.莪术油协同卡铂对人卵巢癌耐药细胞株增殖的影响[J].中国药物与临床,2016,16(7):1012-1014.
[10]阮琼芳,钟桂英.莪术油和常规化疗联合治疗卵巢癌的效果分析[J].医学理论与实践,2018,31(4):554-555.
[11]LI Y F,LI M,LIU S J,et al.Effect of zedoary oil on proliferation and platinum resistance of human ovarian cancer SKOV3 cell line[J].Chin Tradit Patent Med(中成药),2013,35(8):1604-1608.
[12]LI R X,LIU S J,KONG D S,et al.Induction of apoptosis and influence on STAT pathway in human cisplatin-resistantovary cancer cell line by zedoary oil[J].Chin Tradit Patent Med(中成药),2013,35(12):2570-2576.
[13]SHI H Q,HU R W,LOU S X,et al.Overexpression of p53and nm23 in patient with ovarian carcinoma[J].Prac Oncol J(实用肿瘤学杂志),2005,19(4):269-271.
[14]BAI Y,XIONG Y J,LIU X G.Expressions and significances of mitofusin-2,Survivin and nm23 in ovarian cancer[J].Mater Child Health Care China(中国妇幼保健),2014,29(13):2079-2081.
[15]CHUFFA A,GUSTAVO L,FERREIRA M,et al.P-MAPAimmunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling[J].JOvarian Res,2018(11):8-18.
[16]古月娟.紫杉醇联合顺铂治疗对卵巢癌患者血清中TNF-α、IL-6和E-cadherin水平的影响[J].卫生职业教育,2017(22):153-155.
[17]CHEN G W,ZHOU Y X,ZHANG J Q,et al.Study of the expression of VEGF,estrogen receptor and progesterone receptor in endometrial adenocarc and its clinicalpathologic feature[J].J Pract Obstetrics Gynecol(实用妇产科杂志),2016,32(2):96-99.
[18]邓志鸿.PCNA在肿瘤病理学上的应用[J].临床与实验病理学杂志,1994(4):331-333.
[19]ANTONY G K,DUDEK A Z.Interleukin 2 in cancer therapy[J].Curr Med Chem,2013,17(29):3297-3302.
[20]AQBI H F,WALLACE M,SAPPAL S,et al.IFN-γorchestrates tumor elimination,tumor dormancy,tumor escape,and progression[J].J Leukocyte Biol,2018(103):1219-1223.