新四环二萜类化合物－赤霉素衍生物抗肿瘤作用及其机制的研究

中文摘要

化合物G和J是自行合成的新四环二萜类化合物,前期研究显示明显抑制肿瘤细胞生长增殖,并阻滞人早幼粒白血病细胞HL-60和人肺癌细胞A549于G1期.本研究在此基础上评价了化合物G和J的抗肿瘤作用及初步安全性、探索可能的作用机制,取得以下结果:化合物G和J阻滞HL-60和A549细胞于G1期,并诱导细胞凋亡;阻滞HL60于G1期与下调cyclinE蛋白表达有关;G小鼠经口 LD50 为4.1868g/kg；G和J较低剂量显著抑制小鼠肉瘤S180和肝癌H22的生长,抑瘤率超过70%；G较低剂量对人肺癌A549、肝癌HepG2和Bel-7402、结肠癌HCT-116、卵巢癌SKOV3、前列腺癌PC-3及胃癌MKN-28的裸鼠移植瘤生长均显示出不同程度的抑制作用,以对A549、PC-3和MKN-28的作用更显著;G 和 J 明显抑制 TOPOⅠ和TOPOⅡ活性,对TOPOⅠ有更高选择性;G显著抑制HUVEC形成血管的能力.从化合物有效性和安全性两方面考察,提示其具有良好的应用前景,值得进一步研究.关键词:新四环二萜类化合物;抗肿瘤作用;细胞周期阻滞;人癌裸鼠移植瘤

英文摘要

Compounds G and J synthesized from gibberellic acid are novel tetracyclic diterpenoids. Our previous research showed compounds G and J inhibited significantly the proliferation of multiple kinds of human tumor cells and arrested HL60 (human promyelocytic leukemia cells) and A549 (human non-small cell lung adenocarcinoma) in G1 phase. Current study is taken to further evaluate the antitumor activity, acute toxicity and possible mechanism of action of its. We obtained results which are as follows: Compounds G and J arrested HL60 and A549 in G1 phase and induced apoptosis of cells that are involved with downregulation the expression of cyclin E;50% lethal dose of G in mice administrated by oral route is 4.1868g/kg; G and J inhibited significantly the growth of mice sarcoma 180 and hepatoma 22; G inhibited the growth of nude mice xenograft of human lung adenocarcinoma A549、hepatoma HepG2 and Bel-7402、colon carcinoma HCT-116、ovarian cancer SKOV3、prostate cancer PC-3 and gastric cancer MKN-28 at low dosage administrated by oral route; Compounds G and J inhibited significantly the activity of DNA topoisomeraseⅠand Ⅱ,moreover its have stronger effects for topoisomerase. G inhibited markedly the proliferation、migration and capillary formation function of HUVEC. Above results suggested that compound G has potencial app