新型穿心莲内酯衍生物抗肿瘤作用及其机制研究
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摘要
穿心莲内酯(Andrographolide, AD)是我国传统中草药穿心莲(Andrographis paniculata)的主要有效成分之一。近年来,AD作为抗肿瘤、抗病毒药物开发的先导化合物已成为基于AD新药开发的热点之一。为提高AD对肿瘤的细胞毒活性,研究者们针对其第3位、第19位羟基以及第8、第17位双键等位点进行结构修饰,合成了许多新型的化合物。然而,其体内有效性未见提高,有关AD及其衍生物调节肿瘤微环境的抗肿瘤作用机制研究及结构修饰还很欠缺。课题组前期研究发现,AD脱水后的新型C-15位取代衍生物AD-3及其3,19-烟酰酯(AD-2)体外抑制肿瘤细胞与血管内皮细胞的黏附、抗肿瘤细胞迁移及抑制毛细血管通透性增加等活性均较AD大幅提高。本研究采用鸡胚尿囊膜模型、荷H22肝癌小鼠模型、血管内皮细胞ECV304二维、三维迁移模型研究衍生物的体内外抗血管新生作用；采用荷S180肉瘤小鼠模型,荷H22肝癌小鼠模型研究衍生物的抑瘤作用,同时考察衍生物对荷S180肉瘤小鼠免疫器官的影响,并通过ELISA和免疫组化等方法研究化合物对荷瘤小鼠血清及肿瘤组织中相关因子表达的影响,以期阐明AD-2和AD-3调节肿瘤微环境、抗肿瘤血管新生,调节机体免疫力,进而抑制肿瘤组织生长的综合作用机制,为新型穿心莲内酯衍生物的合成及其药效评价,乃至抗肿瘤药物的开发奠定良好的基础。本研究主要结果如下：
1.AD-2和AD-3具有良好的体内抗肿瘤作用,且显著强于其母体化合物AD(P<0.05)。其中AD-3 (0.85 mmol/kg; ig)对S180肉瘤生长的抑制率为53.38±683%,且AD-30.85 mmol/kg和1.10 mmol/kg剂量组的肿瘤扩散级别均为0,与模型组和AD组相比,差异均具有极显著性意义(P<0.01)。说明将AD脱水后,进一步对15位进行修饰可使衍生物的体内抗肿瘤作用显著提高,为基于AD合成抗肿瘤活性更高的衍生物奠定了基础。
2.AD-2和AD-3具有良好的抗血管新生作用。用20μmol/L的AD-2和AD-3处理鸡胚尿囊膜,使血管分支点数量较模型组分别减少了75%和56%,差异具有显著性意义(P<0.05); AD-2 (1.35 mmol/kg; ig)和AD-3 (1.00 mmol/kg;ig)组H22荷瘤小鼠肿瘤组织中的血管指数分别为3.14±1.69和330±1.43,与模型组(4.82±243)和AD组(5.10±2.13)相比,差异均具有显著性意义(P<0.05)；机制研究表明,AD-2和AD-3通过显著上调基质金属蛋白酶MMPs抑制剂TIMP-1,下调血管内皮生长因子VEGF的表达,抑制血管内皮细胞的迁移,阻遏肿瘤组织中微血管的形成,切断肿瘤的氧气和营养供应。
3.AD-2和AD-3能够显著下调荷S180小鼠血清中IL-1β、PGE2及iNOS的表达,抑制肿瘤组织中NF-κB的核位移,抑制肿瘤恶性增殖及血管新生；同时,显著促进荷瘤小鼠血清及肿瘤微环境中肿瘤坏死因子TNF-α的分泌,起到直接抑制肿瘤生长的作用。
4.与环磷酰胺显著不同,实验期间AD-2和AD-3组小鼠体重增加未受影响,且能够在一定程度上调节荷瘤小鼠胸腺及脾脏的免疫指数。AD-2和AD-3提高机体免疫力可能与其抗肿瘤综合效应有关。
综上所述,穿心莲内酯衍生物AD-2、AD-3通过上调肿瘤微环境中TIMP-1 TNF-α的表达,下调VEGF、IL-1β、PGE2、iNOS等的表达,抑制促肿瘤发生发展的NF-κB通路,发挥其抗血管新生、抑制肿瘤的生长及扩散等抗肿瘤作用,而且无明显毒副作用。因而AD-2和AD-3,尤其是AD-3,具备开发为新型高效低毒的调节肿瘤微环境,抑制肿瘤发生发展的抗肿瘤药物的潜力。
Andrographolide (AD) is one of the major active constituents from Andrographis [Andrographis paniculata (Burm. f) Nees], a traditional Chinese herbal medicine. In recent years, AD, as a lead compound for the synthesis of anti-tumor and anti-viral drugs, has become one of the hot spots in the new drug development area. To improve the cytotoxic activity on tumor cells, a lot of derivatives of AD modified in the sites of 3,19-hydroxies and/or 8,17 double bonds have been synthesized by many researchers. However, the in vivo anti-tumor activities of the known derivatives have not been enhanced efficiently. In our previous studies, it was found that two C-15-substituted AD derivatives, AD-3 and AD-2, could significantly inhibit the adhesion between tumor cells and vascular endothelial cells actived by LPS, the migration of tumor cells and the increasing vascular permeability, compared with AD.
In this study, the in vivo anti-angiogenesis effects of AD-2 and AD-3 were investigated by the chick chorioallantoic membrane model (CAM assay) and the H22 tumor-bearing mice model; their in vitro anti-angiogenesis effects were studied by the two-dimensional and three-dimensional migration models. The effects on inhibiting the growth of tumor tissue were also evaluated with both H22 and S180 tumor-bearing mice models. The expression of some cytokines in the tumor tissues and serum of the tumor-bearing mice were evaluated with the immunohistochemistry method and ELISA, respectively, to clarify the complex mechanism of AD-2 and AD-3 on regulating the tumor microenvironment, anti-angiogenesis and enhancing immunity of the mice. These efforts will establish favourable groundwork for the synthesis of novel andrographolide derivatives, even for the development of anti-cancer drugs. The main results are as follows:
1. The in vivo anti-tumor effect of AD-2 and AD-3 were significantly stronger than that of the parent compound AD (P<0.05). AD-3 significantly decreased the weight of tumor tissues by 53.38±6.83% in the dosage of 0.85 mmol/kg (ig). It also significantly inhibited the spread of solid tumor under the dosages of 0.85 mmol/kg (ig) and 1.10 mmol/kg (ig), compared either with the model group or the AD group (P <0.01). These results illustrated that the anti-tumor activity in vivo could be significantly improved by modifying AD in the C-15 site, witch will contribute to the synthesis of AD derivatives with stronger anti-cancer activities.
2. AD-2 and AD-3 showed good anti-angiogenic effects in vitro and in vivo. The vascular branch number in the CAM was significantly reduced about 75% and 56% by AD-2 and AD-3, respectively, compared with that of the model group (P<0.05). In the H22 tumor bearing mice treated with AD-2 (1.35 mmol/kg, ig) and AD-3 (1.00 mmol/kg, ig), the vascular index of the tumor tissue were 3.14±1.69 and 3.30±1.43, separately, which were significantly decreased (P<0.05) when compared with that of the mice in model group (4.82±2.43) and AD group (5.10±2.13).
The results about mechanism studies demonstrated that AD-2 and AD-3 could deter the formation of microvessels in tumor tissues by significantly inhibiting the expression of vascular endothelial growth factor (VEGF), increasing the expression of matrix metalloproteinase inhibitor-1 (TIMP-1), and then inhibiting the migration of vascular endothelial cell ECV304.
3. AD-2 and AD-3 significantly inhibited the NF-κB activation by down-regulating the expression of IL-1β, PGE2 and iNOS in the serum of the S180 tumor bearing mice, then inhibited the proliferation and angiogenesis of the malignant tumor tissues. Meanwhile, the secretion of tumor necrosis factor (TNF-a) also could be significantly enhanced by them to directly inhibit the tumor growth.
4. Unlike cyclophosphamide, the weight increase of mice was not influenced by AD-2 or AD-3, and their immunity index of thymus and spleen had been strengthened in a certain level. The results indicated that AD-2 and AD-3 were able to enhance the immunity of organisms, which was possibly related with their comprehensive effects on anti-tumor.
In conclusion, andrographolide derivatives, AD-2 and AD-3, could inhibit the formation of microvessels, the growth and diffusion of the solid tumor tissues through up-regulating the expression of TNF-a and TIMP-1, down-regulating the expression of VEGF, IL-1(3, PGE2 and iNOS, inhibiting the NF-κB pathway which could promote the tumor genesis and development in the tumor microenvironment. Therefore, AD-2 and AD-3, especially the AD-3, are potentially to be developed as the new anti-tumor drugs, which can regulate the tumor microenvironment and inhibit the tumor development with great efficiency and low toxicity.
1.AD-2和AD-3具有良好的体内抗肿瘤作用,且显著强于其母体化合物AD(P<0.05)。其中AD-3 (0.85 mmol/kg; ig)对S180肉瘤生长的抑制率为53.38±683%,且AD-30.85 mmol/kg和1.10 mmol/kg剂量组的肿瘤扩散级别均为0,与模型组和AD组相比,差异均具有极显著性意义(P<0.01)。说明将AD脱水后,进一步对15位进行修饰可使衍生物的体内抗肿瘤作用显著提高,为基于AD合成抗肿瘤活性更高的衍生物奠定了基础。
2.AD-2和AD-3具有良好的抗血管新生作用。用20μmol/L的AD-2和AD-3处理鸡胚尿囊膜,使血管分支点数量较模型组分别减少了75%和56%,差异具有显著性意义(P<0.05); AD-2 (1.35 mmol/kg; ig)和AD-3 (1.00 mmol/kg;ig)组H22荷瘤小鼠肿瘤组织中的血管指数分别为3.14±1.69和330±1.43,与模型组(4.82±243)和AD组(5.10±2.13)相比,差异均具有显著性意义(P<0.05)；机制研究表明,AD-2和AD-3通过显著上调基质金属蛋白酶MMPs抑制剂TIMP-1,下调血管内皮生长因子VEGF的表达,抑制血管内皮细胞的迁移,阻遏肿瘤组织中微血管的形成,切断肿瘤的氧气和营养供应。
3.AD-2和AD-3能够显著下调荷S180小鼠血清中IL-1β、PGE2及iNOS的表达,抑制肿瘤组织中NF-κB的核位移,抑制肿瘤恶性增殖及血管新生；同时,显著促进荷瘤小鼠血清及肿瘤微环境中肿瘤坏死因子TNF-α的分泌,起到直接抑制肿瘤生长的作用。
4.与环磷酰胺显著不同,实验期间AD-2和AD-3组小鼠体重增加未受影响,且能够在一定程度上调节荷瘤小鼠胸腺及脾脏的免疫指数。AD-2和AD-3提高机体免疫力可能与其抗肿瘤综合效应有关。
综上所述,穿心莲内酯衍生物AD-2、AD-3通过上调肿瘤微环境中TIMP-1 TNF-α的表达,下调VEGF、IL-1β、PGE2、iNOS等的表达,抑制促肿瘤发生发展的NF-κB通路,发挥其抗血管新生、抑制肿瘤的生长及扩散等抗肿瘤作用,而且无明显毒副作用。因而AD-2和AD-3,尤其是AD-3,具备开发为新型高效低毒的调节肿瘤微环境,抑制肿瘤发生发展的抗肿瘤药物的潜力。
Andrographolide (AD) is one of the major active constituents from Andrographis [Andrographis paniculata (Burm. f) Nees], a traditional Chinese herbal medicine. In recent years, AD, as a lead compound for the synthesis of anti-tumor and anti-viral drugs, has become one of the hot spots in the new drug development area. To improve the cytotoxic activity on tumor cells, a lot of derivatives of AD modified in the sites of 3,19-hydroxies and/or 8,17 double bonds have been synthesized by many researchers. However, the in vivo anti-tumor activities of the known derivatives have not been enhanced efficiently. In our previous studies, it was found that two C-15-substituted AD derivatives, AD-3 and AD-2, could significantly inhibit the adhesion between tumor cells and vascular endothelial cells actived by LPS, the migration of tumor cells and the increasing vascular permeability, compared with AD.
In this study, the in vivo anti-angiogenesis effects of AD-2 and AD-3 were investigated by the chick chorioallantoic membrane model (CAM assay) and the H22 tumor-bearing mice model; their in vitro anti-angiogenesis effects were studied by the two-dimensional and three-dimensional migration models. The effects on inhibiting the growth of tumor tissue were also evaluated with both H22 and S180 tumor-bearing mice models. The expression of some cytokines in the tumor tissues and serum of the tumor-bearing mice were evaluated with the immunohistochemistry method and ELISA, respectively, to clarify the complex mechanism of AD-2 and AD-3 on regulating the tumor microenvironment, anti-angiogenesis and enhancing immunity of the mice. These efforts will establish favourable groundwork for the synthesis of novel andrographolide derivatives, even for the development of anti-cancer drugs. The main results are as follows:
1. The in vivo anti-tumor effect of AD-2 and AD-3 were significantly stronger than that of the parent compound AD (P<0.05). AD-3 significantly decreased the weight of tumor tissues by 53.38±6.83% in the dosage of 0.85 mmol/kg (ig). It also significantly inhibited the spread of solid tumor under the dosages of 0.85 mmol/kg (ig) and 1.10 mmol/kg (ig), compared either with the model group or the AD group (P <0.01). These results illustrated that the anti-tumor activity in vivo could be significantly improved by modifying AD in the C-15 site, witch will contribute to the synthesis of AD derivatives with stronger anti-cancer activities.
2. AD-2 and AD-3 showed good anti-angiogenic effects in vitro and in vivo. The vascular branch number in the CAM was significantly reduced about 75% and 56% by AD-2 and AD-3, respectively, compared with that of the model group (P<0.05). In the H22 tumor bearing mice treated with AD-2 (1.35 mmol/kg, ig) and AD-3 (1.00 mmol/kg, ig), the vascular index of the tumor tissue were 3.14±1.69 and 3.30±1.43, separately, which were significantly decreased (P<0.05) when compared with that of the mice in model group (4.82±2.43) and AD group (5.10±2.13).
The results about mechanism studies demonstrated that AD-2 and AD-3 could deter the formation of microvessels in tumor tissues by significantly inhibiting the expression of vascular endothelial growth factor (VEGF), increasing the expression of matrix metalloproteinase inhibitor-1 (TIMP-1), and then inhibiting the migration of vascular endothelial cell ECV304.
3. AD-2 and AD-3 significantly inhibited the NF-κB activation by down-regulating the expression of IL-1β, PGE2 and iNOS in the serum of the S180 tumor bearing mice, then inhibited the proliferation and angiogenesis of the malignant tumor tissues. Meanwhile, the secretion of tumor necrosis factor (TNF-a) also could be significantly enhanced by them to directly inhibit the tumor growth.
4. Unlike cyclophosphamide, the weight increase of mice was not influenced by AD-2 or AD-3, and their immunity index of thymus and spleen had been strengthened in a certain level. The results indicated that AD-2 and AD-3 were able to enhance the immunity of organisms, which was possibly related with their comprehensive effects on anti-tumor.
In conclusion, andrographolide derivatives, AD-2 and AD-3, could inhibit the formation of microvessels, the growth and diffusion of the solid tumor tissues through up-regulating the expression of TNF-a and TIMP-1, down-regulating the expression of VEGF, IL-1(3, PGE2 and iNOS, inhibiting the NF-κB pathway which could promote the tumor genesis and development in the tumor microenvironment. Therefore, AD-2 and AD-3, especially the AD-3, are potentially to be developed as the new anti-tumor drugs, which can regulate the tumor microenvironment and inhibit the tumor development with great efficiency and low toxicity.
引文
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