Inhibition of the proteasome activity by gallium(III) complexes contributes to their anti-prostate tumor effects
Inhibition of the proteasome activity by gallium(III) complexes contributes to their anti-prostate tumor effects
复制标题
DOI：
10.1158/0008-5472.can-07-1813
复制
发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Chen, Di;Frezza, Michael;Dou, Q. Ping
近年来，由于顺铂成功用于对抗各种癌症，对具有潜在抗肿瘤活性的金属配合物的研究变得至关重要。镓（III）和随后开发的含镓（III）络合物在多种恶性肿瘤（特别是淋巴瘤和膀胱癌）中进行测试时显示出良好的抗肿瘤作用。然而，其抗癌作用的分子机制尚未完全了解。我们在此首次报告，蛋白酶体是多种前列腺癌细胞系和人类前列腺癌异种移植物中镓复合物的分子靶标。我们测试了五种镓配合物 (1-5)，其中镓离子以 1:2 (M/L) 的比例与含有吡啶和取代酚盐部分的 WO 不对称配体结合。我们发现复合物5对26S蛋白酶体（IC50，17μmol/L）和纯化的20S（IC50，16μmol/L）蛋白酶体均表现出优异的蛋白酶体抑制活性。一致地，这种效应与前列腺癌细胞的凋亡诱导有关。此外，复合物 5 能够通过抑制小鼠 PC-3 异种移植物的生长 (66%) 发挥相同的体内作用，这与蛋白酶体抑制和细胞凋亡诱导有关。我们的结果强烈表明，镓络合物作为有效的蛋白酶体抑制剂，具有开发成新型抗癌药物的巨大潜力。
The investigation of metal-based complexes with potential antitumor activity has been of paramount importance in recent years due to the successful use of cisplatin against various cancers. Gallium(III) and subsequently developed gallium(III)-containing complexes have shown promising antineoplastic effects when tested in a host of malignancies, specifically in lymphomas and bladder cancer. However, the molecular mechanism responsible for their anticancer effect is yet to be fully understood. We report here for the first time that the proteasome is a molecular target for gallium complexes in a variety of prostate cancer cell lines and in human prostate cancer xenografts. We tested five gallium complexes (1-5) in which the gallium ion is bound to an WO asymmetrical ligand containing pyridine and substituted phenolate moieties in a 1:2 (M/L) ratio. We found that complex 5 showed superior proteasome inhibitory activity against both 26S proteasome (IC50, 17 mu mol/L) and purified 20S (IC50, 16 mu mol/L) proteasome. Consistently, this effect was associated with apoptosis induction in prostate cancer cells. Additionally, complex 5 was able to exert the same effect in vivo by inhibiting growth of PC-3 xenografts in mice (66%), which was associated with proteasome inhibition and apoptosis induction. Our results strongly suggest that gallium complexes, acting as potent proteasome inhibitors, have a great potential to be developed into novel anticancer drugs.