千金子二萜醇p53依赖性抗肿瘤活性及构效关系研究

The p53-dependent antitumor effect and structure-activity relationship of diterpenoids fromEuphorbia lathyris L.

采用噻唑蓝(MTT)法测定6种千金子Lathyrol与Ingenol型二萜醇及其衍生物对不同p53基因型非小细胞肺癌细胞株的抗肿瘤活性,研究千金子二萜醇及其衍生物的构效关系及p53蛋白在千金子二萜醇发挥抗肿瘤活性中的作用与机制。结果表明:天然千金子二萜醇3位羟基成酯后可增加非小细胞肺癌毒性,其中以巨大戟醇甲基丁烯酸酯的细胞毒作用最强。表达p53蛋白可以进一步增加二萜醇酯类衍生物的细胞毒性。在千金子二萜母体醇中引入酯基团可以增强其抗肿瘤活性,同时也能增强其p53依赖的抗肿瘤作用。这一研究为千金子二萜醇作为抗肿瘤先导物来源及其进一步结构优化提供了科学依据。

The present study used MTT assay to determine the anti-tumor activity of six diterpenoids of Euphorbia lathyris L.including lathyrol and ingenol type-diterpenoids and their derivatives on non-small-cell lung cancer cells with different p53 status,which is aimed to investigate the p53-dependent antitumor effect and structure-activity relationship of diterpenoids fromEuphorbia lathyris L.,as lead compounds for cancer treatment.As a result,we found that esterification of hydroxyl groups(3-OH)could significantly increase the cytotoxicity,and Ingenol-3-angelate showed potent activity to inhibit proliferation of tumor cells.Furthermore,expression of p53 protein could amplify the cytotoxicity of the diterpenoids as well as ester derivatives.Therefore,introduction of ester groups in the diterpenoid skeleton would enhance p53-dependent anti-tumor effect of diterpenoids of E.lathyris.Our study provides strong evidence for the development of potential antitumor candidates from diterpenoid analogues of E.lathyris.