PG490 (triptolide) cooperates with tumor necrosis factor-α to induce apoptosis in tumor cells
PG490 (triptolide) cooperates with tumor necrosis factor-α to induce apoptosis in tumor cells
复制标题
DOI：
10.1074/jbc.274.19.13451
复制
发表时间：
1999-05-07
影响因子：
4.8
通讯作者：
Rosen, GD
中科院分区：
文献类型：
--
作者：
Lee, KY;Chang, WT;Rosen, GD
实体瘤的治疗进展缓慢且零星。常规化疗对实体瘤的疗效有限，因为肿瘤经常有p53基因突变。此外，化疗只会杀死快速分裂的细胞。然而，肿瘤坏死因子（TNF）家族成员诱导细胞凋亡与p53表型无关。不幸的是，tnf - α的细胞毒性受到其对NF-kappa B的激活和NF-kappa B的激活的限制，NF-kappa B具有促炎作用。我们已经鉴定出一种名为PG490的化合物，它由纯化的雷公雷甲素组成，可诱导肿瘤细胞凋亡并使肿瘤细胞对tnf - α诱导的凋亡敏感，PG490有效抑制tnf - α诱导的NF-kappa B的激活，PG490还阻断tnf - α介导的c-IAP2 （hiap-1）和c-IAP1 （hiap-2）的诱导。作为凋亡抑制剂（IAP）家族的成员，有趣的是，PG490不阻断NF-kappa B的DNA结合，但它阻断NF-kappa B的反活化。我们鉴定的一种阻断tnf - α诱导的NP-kappa B活化的化合物可能增强tnf - α对肿瘤的细胞毒性，并限制其促炎作用。
Progress in the treatment of solid tumors has been slow and sporadic. The efficacy of conventional chemotherapy in solid tumors is limited because tumors frequently have mutations in the p53 gene. Also, chemotherapy only kills rapidly dividing cells. Members of the tumor necrosis factor (TNF) family, however, induce apoptosis regardless of the p53 phenotype. Unfortunately, the cytotoxicity of TNF-alpha is limited by its activation of NF-kappa B and activation of NF-kappa B is proinflammatory, We have identified a compound called PG490, that is composed of purified triptolide, which induces apoptosis in tumor cells and sensitizes tumor cells to TNF-alpha-induced apoptosis, PG490 potently inhibited TNF-alpha-induced activation of NF-kappa B, PG490 also blocked TNF-alpha-mediated induction of c-IAP2 (hiap-1) and c-IAP1 (hiap-2), members of the inhibitor of apoptosis (IAP) family, interestingly, PG490 did not block DNA binding of NF-kappa B, but it blocked transactivation of NF-kappa B, Our identification of a compound that blocks TNF-alpha-induced activation of NP-kappa B may enhance the cytotoxicity of TNF-alpha on tumors in vivo and limit its proinflammatory effects.