Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p300 complex in a preclinical model of prostate cancer.
Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p300 complex in a preclinical model of prostate cancer.
复制标题
DOI：
10.1186/1476-4598-13-91
复制
发表时间：
2014-04-28
期刊：
影响因子：
37.3
通讯作者：
Figg WD
中科院分区：
文献类型：
--
作者：
Reece KM;Richardson ED;Cook KM;Campbell TJ;Pisle ST;Holly AJ;Venzon DJ;Liewehr DJ;Chau CH;Price DK;Figg WD
缺氧诱导因子-1 α（hypoxia inducible factor-1 alpha，HIF-1α）的下游靶点在肿瘤进展和血管生成中起重要作用。因此，抑制HIF介导的转录具有治疗癌症的潜力。抑制HIF活性的一个有吸引力的策略是破坏HIF-1α/p300复合物，因为p300是低氧诱导转录的关键共激活因子。表二硫代二酮哌嗪（ETP）家族的几种天然产物已被证明在体外破坏HIF-1α/p300复合物;即胶毒素、毛壳菌素和毛壳菌素。在这里，我们进一步的特点，这些ETP的抗血管生成和抗肿瘤作用的分子机制，使用前列腺癌的临床前模型。在大鼠主动脉环血管生成试验中，gliotoxin，毛壳菌素，和chetomin显着抑制微血管生长的GI 50分别为151，8和20 nM。前列腺癌细胞提取物的体外免疫共沉淀研究表明，这些化合物破坏了HIF-1α/p300复合物。通过在mRNA和蛋白水平上测定HIF-1α靶基因的表达来评价抑制HIF-1α/p300相互作用的下游效应。通过ELISA检测到处理细胞培养基中分泌的VEGF水平呈剂量依赖性降低，随后通过半定量实时PCR证实了VEGFA、LDHA和ENO 1 HIF-1α靶基因的下调。最后，在携带前列腺肿瘤异种移植物的小鼠中用ETP治疗导致肿瘤生长的显著抑制。这些结果表明，直接靶向HIF-1α/p300复合物的ETP可能是一种有效的抑制血管生成和肿瘤生长的方法。
The downstream targets of hypoxia inducible factor-1 alpha (HIF-1α) play an important role in tumor progression and angiogenesis. Therefore, inhibition of HIF-mediated transcription has potential in the treatment of cancer. One attractive strategy for inhibiting HIF activity is the disruption of the HIF-1α/p300 complex, as p300 is a crucial coactivator of hypoxia-inducible transcription. Several members of the epidithiodiketopiperazine (ETP) family of natural products have been shown to disrupt the HIF-1α/p300 complex in vitro; namely, gliotoxin, chaetocin, and chetomin. Here, we further characterized the molecular mechanisms underlying the antiangiogenic and antitumor effects of these ETPs using a preclinical model of prostate cancer. In the rat aortic ring angiogenesis assay, gliotoxin, chaetocin, and chetomin significantly inhibited microvessel outgrowth at a GI50 of 151, 8, and 20 nM, respectively. In vitro co-immunoprecipitation studies in prostate cancer cell extracts demonstrated that these compounds disrupted the HIF-1α/p300 complex. The downstream effects of inhibiting the HIF-1α/p300 interaction were evaluated by determining HIF-1α target gene expression at the mRNA and protein levels. Dose-dependent decreases in levels of secreted VEGF were detected by ELISA in the culture media of treated cells, and the subsequent downregulation of VEGFA, LDHA, and ENO1 HIF-1α target genes were confirmed by semi-quantitative real-time PCR. Finally, treatment with ETPs in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. These results suggest that directly targeting the HIF-1α/p300 complex with ETPs may be an effective approach for inhibiting angiogenesis and tumor growth.
登录
查看更多内容
影响因子：
8
作者：
Semenza, G. L.
通讯作者：
Semenza, G. L.
DOI：
10.3322/caac.20075
发表时间：
2010-07
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Cook KM;Figg WD
通讯作者：
Figg WD
影响因子：
6.7
作者：
Lee, HJ;Lee, JH;Lee, JJ
通讯作者：
Lee, JJ
影响因子：
13.5
作者：
Lee, Yoon-Mi;Lim, Ji-Hong;Park, Jong-Wan
通讯作者：
Park, Jong-Wan
影响因子：
3.9
作者：
Patiar, Shalini;Harris, Adrian L.
通讯作者：
Harris, Adrian L.