茶多酚抗肺癌效应及抗肺癌血管生成相关信号通路研究
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摘要
1背景与目的
肺癌为全球第一大恶性肿瘤,其中非小细胞肺癌(NSCLC)占80%以上,多数患者发现时已属于晚期,失去了手术根治的机会,且临床上以化放疗为主的常规治疗对NSCLC敏感性较差。然而肺癌组织血管丰富,肿瘤血管抑制剂在肺癌治疗中具有一定优势而备受人们瞩目。茶叶具有化痰、解毒功能,在药食同源、药证对应中医理论指导下,将其“化痰与解毒”功能拓展用于恶性肿瘤的临床与实验研究中,发现其主要生物活性成分茶多酚(TP)能够选择性地抑制肿瘤血管生成。为进一步研究茶多酚抗肺癌的效应与机制,探究其对肺癌新生血管生成关键转录因子及其信号通路的影响,我们开展了一系列体外、体内实验,观察茶多酚对NSCLC细胞系以及小鼠肺癌移植瘤的影响,并以NF-κB、AP-1及其通路为主线,研究茶多酚抗NSCLC血管生成的可能靶点。
2方法
体外实验部分,通过Methylene Blue法检测TP及其主要成分EGCG对NSCLC细胞生长的抑制作用,并观察TP对KB-MDR多药耐药细胞生长的影响,探究其是否产生或逆转多药耐药；同时采用Luciferase Reporter System研究茶多酚对NF-κB信号通路、AP-1信号通路、TLR-2信号通路、TLR-4信号通路和Nrf2信号通路等的影响。
体内实验部分,建立C57BL/6小鼠Lewis肺癌移植瘤模型,以血管生成抑制剂沙利度胺为对照,将48只荷瘤小鼠随机分入模型对照组(相同容量的生理盐水)、沙利度胺组(76mg/kg/d)、TP低剂量组(112.5mg/kg/d)、TP高剂量组(337.5mg/kg/d)、TP低剂量联合沙利度胺组(112.5mg/kg/d+76mg/kg/d)以及TP高剂量联合沙利度胺组(337.5mg/kg/d+76mg/kg/d)6个组,连续灌胃给药10天,观察各组移植瘤生长情况,并以免疫组化法检测NF-κB、COX-2、Survivin. Akt-2、C-Jun、MMP-2、TIMP-2等肿瘤血管生成相关因子的表达水平,以探讨TP抗肺癌血管生成的可能信号传导通路及靶点。
3结果
实验结果显示：(1)TP抑制NCI-H1299、NCI-H522.A549和EKVX细胞系生长的IC50分别为11.8±2.5μg/ml.26.1±5.6μg/ml.61.5±12.7μg/ml和9.4±0.9μg/ml;EGCG抑制NCI-H1299.NCI-H522.A549和EKVX细胞系生长的IC50分别为20.4±5.2μM、51.3±12.7μM、117.5±28.8μM和20.0±4.7μM；(2)TP抑制KB与KB-MDR细胞生长的1C50分别为33.5±7.8μg/ml.33.3±4.9μg/ml,EGCG抑制KB与KB-MDR细胞生长的IC50分别为46±11μM.60.0±14μM,它们对KB与KB-MDR细胞生长抑制作用无差别(P>0.05)；同时加入TP或EGCG均未能逆转KB-MDR(?)细胞株对Taxol的耐药性；(3)TP抑制TNF-α激活的NF-κB信号通路的IC50为51μg/ml抑制TPA激活的AP-1信号通路的1C50为18μg/ml,TP抑制PGN激活的TLR-2信号通路的IC50为83μg/ml,TP抑制LPS激活的TLR-4信号通路的IC50为78μg/ml,对Nrf-2和Ubiquitin信号通路未见明显影响；(4)与模型对照组相比,TP高剂量联合沙利度胺组移植瘤的瘤重显著降低(P<0.05),其抑瘤率约44.32%;(5)与模型对照组相比,TP高剂量联合沙利度胺组NF-κB表达显著下降(P<0.05),COX-2表达在TP低剂量组及联合用药各组均显著下降(P<0.05),Survivin表达在沙利度胺组和TP高剂量联合沙利度胺组明显减低(P<0.05),在TP高剂量组下降更为显著(P<0.01)；Akt-2表达在实验各组无明显改变(P>0.05)；(6)与模型对照组比较,TP各组及联合用药各组能显著下调肿瘤组织MMP-2蛋白表达(P<0.05),TP高剂量联合沙利度胺组能显著上调TIMP-2蛋白表达(P<0.05),TP高、低剂量组的MMP-2/TIMP-2比值均明显降低,TP高剂量联合沙利度胺组比值下降更为显著,C-Jun表达在沙利度胺组和TP高剂量联合沙利度胺组显著下降(P<0.05)。
4结论
研究发现：(1)TP及其主要成分EGCG对NSCLC细胞系具有一定抑制作用；(2)TP对多药耐药细胞敏感,但不未能逆转多药耐药；(3)TP能够不同程度地抑制NF-κB、AP-1、TLR-2、TLR-4等相关信号通路的传导,以NF-κB、AP-1更为明显;(4)TP高剂量联合沙利度胺能够明显抑制移植瘤生长；(5)NF-κB信号传导通路可能为TP抗肿瘤血管生成的关键途径,其机制与抑制NF-κB活化、降低COX-2表达并降低内皮细胞Survivin表达有关；(6)TP抗血管生成机制可能与下调MMP-2表达、上调TIMP-2表达、调整MMP-2/TIMP-2比值失衡相关,其他途径是通过除C-Jun/AP-1以外的其他信号通路。综上所述,茶多酚对能够在一定程度上抑制肺癌生长及肺癌血管生成,其抗肿瘤血管生成是一个多项环节、多个靶点、多条信号通路同时作用的复杂过程,茶多酚抗新生血管生成具有天然药物广谱、安全等作用特点,符合现代医学多重靶向作用理念,值得进一步深入研究。
OBJECTIVE
Lung cancer is the first cause of cancer death and the most common cancer worldwide, of which more than80%is non-small cell lung cancer (NSCLC). Patients are usually diagnosed in advanced stage and most of them are not sensitive to conventional therapy such as chemotherapy and radiotherapy. Despite of this poor clinical outcome. lung cancer tissue is rich in blood vessels, which provides advantage for the anti-angiogenesis treatment. Tea is the second popular drink after water in the world. It is regarded as an herb in Traditional Chinese Medicine. According to the Syndrome Differentiation Theory, tea has the function of clearing the phlegm and detoxification, which is critical for cancer treatment. And results from our clinical trial as well as lab experiments on Tea Polyphenols (TPs) showed it had anti-cancer and anti-angiogenesis effects. In order to further investigate TP's effects on the tumor growth and angiogenesis of NSCLC and to explore its possible transduction signaling pathways, we carried out a series of in vitro and in vivo experiments with a focus on NF-κB, AP-1and their related pathways.
METHODS
For in vitro experiments, the effects of TP and its main component EGCG on growth inhibition of NSCLC were tested by Methylene Blue Assay. KB and KB-MDR cell lines were used to test TP's sensitivity and possible reversal effects of multidrug resistance. Luciferase Reporter System was used to study the signaling pathways of TP. For in vivo experiments, Lewis lung cancer xenograft model was established and48implanted mice were randomly assigned to six groups, namely model control group (0.9%NaCl), Thalidomide group (76mg/kg/d), TP low-dose group (112.5mg/kg/d), TP high-dose group (337.5mg/kg/d), TP low-dose combined with Thalidomide group (112.5mg/kg/d+76mg/kg/d), and TP high-dose combined with Thalidomide group (337.5mg/kg/d+76mg/kg/d). All groups received continuous ten-day orally administrated treatment accordingly. Toxicity and anticancer effects were observed and calculated, while different factors (NF-κB, COX-2, Survivin, Akt-2, C-Jun, MMP-2and TIMP-2) related to anti-angiogenesis pathways were tested applying immunohistochemical techniques.
RESULTS
Experimental results showed that:(1) The IC50of cell growth inhibition for TP in NCI-H1299, NCI-H522, A549and EKVX cell lines were11.8±2.5μg/ml,26.1±5.6μg/ml,61.5±12.7μg/ml and9.4±0.9μg/ml respectively; and for EGCG were20.4±5.2μM,51.3±12.7μM,117.5±28.8μM and20.0±4.7μM respectively.(2) There was no significant difference of TP and EGCG's IC50between KB and KB-MDR cell lines, and no reversal effects on KB-MDR's resistance to Taxol were indicated when treated with TP and EGCG.(3) TP inhibited TNF-α induced NF-kB signaling with an IC50of51μg/ml, inhibited TPA induced AP-I signaling with an IC50of18μg/ml, suppressed PGN induced TLR-2signaling with an IC50of83μg/ml, and suppressed ITS induced TLR-4signaling with an IC50of78μg/ml, correspondingly. No significantly changes were showed for Nrf2and Ubiquitin signaling.(4) Compared with model control group. IT high-dose combined vvith Thalidomide group significantly inhibited tumor growth (P<0.05), with a tumor inhibition rate of approximately44%.(5) Comparing to model control group, TP high dose combined with Thalidomide group significantly reduced the expression of NF-kB. COX-2and Survivin (P<0.05), while the expression of Akt-2were not obviously changed in all groups.(6) Comparing to model control group, MMP-2expression was down-regulated in IP groups and their Thalidomide combination groups (P<0.05). whereas TIMP-2expression was up-regulated in IT high close combined with Thalidomide group (P<0.05). there were higher MMP-2/TIMP-2ratios in all IP involved groups, especially for IP high-dose combined with Thalidomide group.
CONCLUSION
According to our studies, we find out (1) TP and LGCG could inhibit the growth NSCLC cell lines;(2) IP is not resistance to KB-MDR. but cannot reverse its multi-drug resistance either:(3) TP could inhibit NF-kB, AP-1, TLR-2, TLR-4signaling pathways, with a higher potency for NI'-kB and AP-1pathways;(4) TP high dose combined with Thalidomide can inhibit Lewis lung tumor growth;(5) NF-kB signaling pathway is a key pathway of IP's anti-angiogenesis effects, in which it inhibits NF-kB activation, reduces COX-2expression and Survivin expression in endothclial cells;(6) The anti-angiogenesis effect of TP could also related to down-regulation of MMP-2expression, up-regulation of TIMP-2expression, and restoring of MMP-2/TIMP-2balance. To sum up, Tea polyphenols have been confirmed to have tumor inhibition effect on NSCLC to a certain extent, and it has the potential to be a multi-targeted anti-angiogenesis agent affecting various signaling pathways at different levels.
肺癌为全球第一大恶性肿瘤,其中非小细胞肺癌(NSCLC)占80%以上,多数患者发现时已属于晚期,失去了手术根治的机会,且临床上以化放疗为主的常规治疗对NSCLC敏感性较差。然而肺癌组织血管丰富,肿瘤血管抑制剂在肺癌治疗中具有一定优势而备受人们瞩目。茶叶具有化痰、解毒功能,在药食同源、药证对应中医理论指导下,将其“化痰与解毒”功能拓展用于恶性肿瘤的临床与实验研究中,发现其主要生物活性成分茶多酚(TP)能够选择性地抑制肿瘤血管生成。为进一步研究茶多酚抗肺癌的效应与机制,探究其对肺癌新生血管生成关键转录因子及其信号通路的影响,我们开展了一系列体外、体内实验,观察茶多酚对NSCLC细胞系以及小鼠肺癌移植瘤的影响,并以NF-κB、AP-1及其通路为主线,研究茶多酚抗NSCLC血管生成的可能靶点。
2方法
体外实验部分,通过Methylene Blue法检测TP及其主要成分EGCG对NSCLC细胞生长的抑制作用,并观察TP对KB-MDR多药耐药细胞生长的影响,探究其是否产生或逆转多药耐药；同时采用Luciferase Reporter System研究茶多酚对NF-κB信号通路、AP-1信号通路、TLR-2信号通路、TLR-4信号通路和Nrf2信号通路等的影响。
体内实验部分,建立C57BL/6小鼠Lewis肺癌移植瘤模型,以血管生成抑制剂沙利度胺为对照,将48只荷瘤小鼠随机分入模型对照组(相同容量的生理盐水)、沙利度胺组(76mg/kg/d)、TP低剂量组(112.5mg/kg/d)、TP高剂量组(337.5mg/kg/d)、TP低剂量联合沙利度胺组(112.5mg/kg/d+76mg/kg/d)以及TP高剂量联合沙利度胺组(337.5mg/kg/d+76mg/kg/d)6个组,连续灌胃给药10天,观察各组移植瘤生长情况,并以免疫组化法检测NF-κB、COX-2、Survivin. Akt-2、C-Jun、MMP-2、TIMP-2等肿瘤血管生成相关因子的表达水平,以探讨TP抗肺癌血管生成的可能信号传导通路及靶点。
3结果
实验结果显示：(1)TP抑制NCI-H1299、NCI-H522.A549和EKVX细胞系生长的IC50分别为11.8±2.5μg/ml.26.1±5.6μg/ml.61.5±12.7μg/ml和9.4±0.9μg/ml;EGCG抑制NCI-H1299.NCI-H522.A549和EKVX细胞系生长的IC50分别为20.4±5.2μM、51.3±12.7μM、117.5±28.8μM和20.0±4.7μM；(2)TP抑制KB与KB-MDR细胞生长的1C50分别为33.5±7.8μg/ml.33.3±4.9μg/ml,EGCG抑制KB与KB-MDR细胞生长的IC50分别为46±11μM.60.0±14μM,它们对KB与KB-MDR细胞生长抑制作用无差别(P>0.05)；同时加入TP或EGCG均未能逆转KB-MDR(?)细胞株对Taxol的耐药性；(3)TP抑制TNF-α激活的NF-κB信号通路的IC50为51μg/ml抑制TPA激活的AP-1信号通路的1C50为18μg/ml,TP抑制PGN激活的TLR-2信号通路的IC50为83μg/ml,TP抑制LPS激活的TLR-4信号通路的IC50为78μg/ml,对Nrf-2和Ubiquitin信号通路未见明显影响；(4)与模型对照组相比,TP高剂量联合沙利度胺组移植瘤的瘤重显著降低(P<0.05),其抑瘤率约44.32%;(5)与模型对照组相比,TP高剂量联合沙利度胺组NF-κB表达显著下降(P<0.05),COX-2表达在TP低剂量组及联合用药各组均显著下降(P<0.05),Survivin表达在沙利度胺组和TP高剂量联合沙利度胺组明显减低(P<0.05),在TP高剂量组下降更为显著(P<0.01)；Akt-2表达在实验各组无明显改变(P>0.05)；(6)与模型对照组比较,TP各组及联合用药各组能显著下调肿瘤组织MMP-2蛋白表达(P<0.05),TP高剂量联合沙利度胺组能显著上调TIMP-2蛋白表达(P<0.05),TP高、低剂量组的MMP-2/TIMP-2比值均明显降低,TP高剂量联合沙利度胺组比值下降更为显著,C-Jun表达在沙利度胺组和TP高剂量联合沙利度胺组显著下降(P<0.05)。
4结论
研究发现：(1)TP及其主要成分EGCG对NSCLC细胞系具有一定抑制作用；(2)TP对多药耐药细胞敏感,但不未能逆转多药耐药；(3)TP能够不同程度地抑制NF-κB、AP-1、TLR-2、TLR-4等相关信号通路的传导,以NF-κB、AP-1更为明显;(4)TP高剂量联合沙利度胺能够明显抑制移植瘤生长；(5)NF-κB信号传导通路可能为TP抗肿瘤血管生成的关键途径,其机制与抑制NF-κB活化、降低COX-2表达并降低内皮细胞Survivin表达有关；(6)TP抗血管生成机制可能与下调MMP-2表达、上调TIMP-2表达、调整MMP-2/TIMP-2比值失衡相关,其他途径是通过除C-Jun/AP-1以外的其他信号通路。综上所述,茶多酚对能够在一定程度上抑制肺癌生长及肺癌血管生成,其抗肿瘤血管生成是一个多项环节、多个靶点、多条信号通路同时作用的复杂过程,茶多酚抗新生血管生成具有天然药物广谱、安全等作用特点,符合现代医学多重靶向作用理念,值得进一步深入研究。
OBJECTIVE
Lung cancer is the first cause of cancer death and the most common cancer worldwide, of which more than80%is non-small cell lung cancer (NSCLC). Patients are usually diagnosed in advanced stage and most of them are not sensitive to conventional therapy such as chemotherapy and radiotherapy. Despite of this poor clinical outcome. lung cancer tissue is rich in blood vessels, which provides advantage for the anti-angiogenesis treatment. Tea is the second popular drink after water in the world. It is regarded as an herb in Traditional Chinese Medicine. According to the Syndrome Differentiation Theory, tea has the function of clearing the phlegm and detoxification, which is critical for cancer treatment. And results from our clinical trial as well as lab experiments on Tea Polyphenols (TPs) showed it had anti-cancer and anti-angiogenesis effects. In order to further investigate TP's effects on the tumor growth and angiogenesis of NSCLC and to explore its possible transduction signaling pathways, we carried out a series of in vitro and in vivo experiments with a focus on NF-κB, AP-1and their related pathways.
METHODS
For in vitro experiments, the effects of TP and its main component EGCG on growth inhibition of NSCLC were tested by Methylene Blue Assay. KB and KB-MDR cell lines were used to test TP's sensitivity and possible reversal effects of multidrug resistance. Luciferase Reporter System was used to study the signaling pathways of TP. For in vivo experiments, Lewis lung cancer xenograft model was established and48implanted mice were randomly assigned to six groups, namely model control group (0.9%NaCl), Thalidomide group (76mg/kg/d), TP low-dose group (112.5mg/kg/d), TP high-dose group (337.5mg/kg/d), TP low-dose combined with Thalidomide group (112.5mg/kg/d+76mg/kg/d), and TP high-dose combined with Thalidomide group (337.5mg/kg/d+76mg/kg/d). All groups received continuous ten-day orally administrated treatment accordingly. Toxicity and anticancer effects were observed and calculated, while different factors (NF-κB, COX-2, Survivin, Akt-2, C-Jun, MMP-2and TIMP-2) related to anti-angiogenesis pathways were tested applying immunohistochemical techniques.
RESULTS
Experimental results showed that:(1) The IC50of cell growth inhibition for TP in NCI-H1299, NCI-H522, A549and EKVX cell lines were11.8±2.5μg/ml,26.1±5.6μg/ml,61.5±12.7μg/ml and9.4±0.9μg/ml respectively; and for EGCG were20.4±5.2μM,51.3±12.7μM,117.5±28.8μM and20.0±4.7μM respectively.(2) There was no significant difference of TP and EGCG's IC50between KB and KB-MDR cell lines, and no reversal effects on KB-MDR's resistance to Taxol were indicated when treated with TP and EGCG.(3) TP inhibited TNF-α induced NF-kB signaling with an IC50of51μg/ml, inhibited TPA induced AP-I signaling with an IC50of18μg/ml, suppressed PGN induced TLR-2signaling with an IC50of83μg/ml, and suppressed ITS induced TLR-4signaling with an IC50of78μg/ml, correspondingly. No significantly changes were showed for Nrf2and Ubiquitin signaling.(4) Compared with model control group. IT high-dose combined vvith Thalidomide group significantly inhibited tumor growth (P<0.05), with a tumor inhibition rate of approximately44%.(5) Comparing to model control group, TP high dose combined with Thalidomide group significantly reduced the expression of NF-kB. COX-2and Survivin (P<0.05), while the expression of Akt-2were not obviously changed in all groups.(6) Comparing to model control group, MMP-2expression was down-regulated in IP groups and their Thalidomide combination groups (P<0.05). whereas TIMP-2expression was up-regulated in IT high close combined with Thalidomide group (P<0.05). there were higher MMP-2/TIMP-2ratios in all IP involved groups, especially for IP high-dose combined with Thalidomide group.
CONCLUSION
According to our studies, we find out (1) TP and LGCG could inhibit the growth NSCLC cell lines;(2) IP is not resistance to KB-MDR. but cannot reverse its multi-drug resistance either:(3) TP could inhibit NF-kB, AP-1, TLR-2, TLR-4signaling pathways, with a higher potency for NI'-kB and AP-1pathways;(4) TP high dose combined with Thalidomide can inhibit Lewis lung tumor growth;(5) NF-kB signaling pathway is a key pathway of IP's anti-angiogenesis effects, in which it inhibits NF-kB activation, reduces COX-2expression and Survivin expression in endothclial cells;(6) The anti-angiogenesis effect of TP could also related to down-regulation of MMP-2expression, up-regulation of TIMP-2expression, and restoring of MMP-2/TIMP-2balance. To sum up, Tea polyphenols have been confirmed to have tumor inhibition effect on NSCLC to a certain extent, and it has the potential to be a multi-targeted anti-angiogenesis agent affecting various signaling pathways at different levels.
引文
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