A heterometallic ruthenium-gold complex displays antiproliferative, antimigratory, and antiangiogenic properties and inhibits metastasis and angiogenesis-associated proteases in renal cancer.
A heterometallic ruthenium-gold complex displays antiproliferative, antimigratory, and antiangiogenic properties and inhibits metastasis and angiogenesis-associated proteases in renal cancer.
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DOI：
10.1007/s00775-018-1546-8
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Contel M
中科院分区：
文献类型：
--
作者：
Elie BT;Pechenyy Y;Uddin F;Contel M
杂环化合物被设计成将不同金属物质的化学治疗特性利用到单个分子中。基于Au-N-杂环卡宾（NHC）片段[Cl 2（p-cymene）Ru（μ-dppm）Au（NHC）] ClO 4的钌-金（Ru-Au）族化合物被认为是将Au-NHC基化合物的已知抗增殖和细胞毒性性质与特定Ru基化合物的抗迁移、抗转移和抗血管生成特性联合收割机结合。根据最近的研究，这些Ru-Au-NHC配合物具有作为体外结肠直肠癌和肾癌化疗药物的潜力，我们在此报道了所选化合物[Cl 2（p-cymene）Ru（μ-dppm）Au（IMes）] ClO 4（RANCE-1，1）的机制。使用人肾透明细胞癌细胞系（Caki-1）在体外进行研究。这些研究表明，钌化合物RANCE-1（1）的细胞毒性显著高于Ru（2）或Au（3）单核苷酸衍生物。RANCE-1显著抑制转移所必需的迁移、侵袭和血管生成。研究发现，RANCE-1通过抑制组织蛋白酶以及在癌症发病机制中发挥关键作用的金属蛋白酶MMP和ADAM来干扰细胞周蛋白质水解。RANCE-1还抑制线粒体蛋白TrxR，该蛋白通常在癌细胞中过表达并促进凋亡逃避。我们发现，虽然金诺芬在Caki-1肾癌细胞中扰乱迁移和侵袭的程度与RANCE-1（1）相似，但RANCE-1（1）抑制抗血管生成形成和VEGF表达。我们发现Auranofin和RANCE-1（1）具有不同的蛋白水解谱。总之，RANCE-1是一种非常有希望的候选药物，可用于肾癌的进一步临床前评价。
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic carbene (NHC) fragments [Cl2(p-cymene)Ru(μ-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au-NHC-based compounds and the antimigratory, antimetastatic and antiangiogenic characteristic of specific Ru-based compounds. Following recent studies of the anticancer efficacies of these Ru–Au-NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2(p-cymene)Ru(μ-dppm)Au(IMes)]ClO4 (RANCE-1, 1). The studies were carried out in vitro using a human clear cell renal carcinoma cell line (Caki-1). These studies indicate that bimetallic compound RANCE-1 (1) is significantly more cytotoxic than the Ru (2) or Au (3) monometallic derivatives. RANCE-1 significantly inhibits migration, invasion and angiogenesis, which are essential for metastasis. RANCE-1 was found to disturb pericellular proteolysis by inhibiting cathepsins, and the metalloproteases MMP and ADAM which play key roles in the etiopathogenesis of cancer. RANCE-1 also inhibits the mitochondrial protein TrxR that is often overexpressed in cancer cells and facilitates apoptosis evasion. We found that while Auranofin perturbed migration and invasion to similar degrees as RANCE-1 (1) in Caki-1 renal cancer cells, RANCE-1 (1) inhibited antiangiogenic formation and VEGF expression. We found that Auranofin and RANCE-1 (1) have distinct proteolytic profiles. In summary, RANCE-1 constitutes a very promising candidate for further preclinical evaluations in renal cancer.
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影响因子：
12.8
作者：
Lim, HW;Hong, S;Lim, CJ
通讯作者：
Lim, CJ
影响因子：
16.6
作者：
Kwong, Wai-Lun;Lam, Kar-Yee;Che, Chi-Ming
通讯作者：
Che, Chi-Ming
影响因子：
37.3
作者：
Cheng X;Holenya P;Can S;Alborzinia H;Rubbiani R;Ott I;Wölfl S
通讯作者：
Wölfl S
影响因子：
8
作者：
Denkert, C;Fürstenberg, A;Hauptmann, S
通讯作者：
Hauptmann, S
DOI：
10.1039/c5cc09718e
发表时间：
2016-02-21
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Fernández-Gallardo J;Elie BT;Sanaú M;Contel M
通讯作者：
Contel M