In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis
In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis
复制标题
穿心莲内酯衍生物ADN-9对肝癌的体内抑制活性及其抑制肿瘤血管生成的机制
DOI：
10.1016/j.taap.2017.04.022
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发表时间：
2017
影响因子：
3.8
通讯作者：
Dai Guifu
中科院分区：
文献类型：
--
作者：
Yang Wei;Zhao Jin;Wang Yake;Xu Haiwei;Wu Zhenwei;Hu Yangyang;Jiang Kunkun;Shen Pengpeng;Ma Cuiyun;Guan Zhenzhen;Zhang Yan;Ma Jiahui;Shang Ning;Yan Guangming;Wang Zhenji;Dai Guifu
众所周知，肝癌是一种高度侵袭性的恶性肿瘤，预后差。穿心莲内酯（Andrographylaxis，AD）是穿心莲（Andrographis paniculata（Burm. F.），AD是一种潜在的抗癌药效团，合成对癌细胞具有更好细胞毒性的AD衍生物已引起人们的广泛关注。本研究采用小鼠肝癌H22原位移植瘤模型和皮下移植瘤模型，评价了AD的15-亚苄基取代衍生物ADN-9对小鼠肝癌H22生长和转移的体内抑制作用，并进一步研究了ADN-9在体内和体外的抗血管生成作用及其相关机制。重要的是，ADN-9显著抑制原位和皮下异种移植肿瘤的生长和转移，并且在用100 mg/kg ADN-9（ig.）已降至正常水平。在小鼠皮下移植瘤模型中，ADN-9在缩小肿瘤、抑制H22细胞侵袭转移、降低MVD和促进肿瘤细胞凋亡等方面的作用均强于AD。ADN-9对VEGF诱导的HUVECs迁移和毛细血管样管形成的抑制作用强于AD，进一步证实ADN-9可能通过抑制VEGF/VEGFR2/AKT信号通路发挥作用。本研究提供了第一个证据，表明15-取代的AD衍生物在肝癌的治疗性治疗中比母体化合物更有前途。
It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component ofAndrographis paniculata(Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated thein vivoinhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9in vivoandin vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100 mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.