以定制钌配合物靶向癌症干细胞氧化磷酸化作为一种新的抗癌策略。 - Suppr | 超能文献

Abstract

BACKGROUND

Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking.

METHODS

The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action.

RESULTS

We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration.

CONCLUSIONS

Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

摘要

背景

我们团队之前的研究表明，氧化磷酸化（OXPHOS）是胰腺癌干细胞（CSCs）满足其能量需求的主要途径；因此，氧化磷酸化是这些高致瘤性细胞的致命弱点。不幸的是，针对CSCs中氧化磷酸化的疗法尚不存在。

方法

使用8种患者来源的异种移植模型（PDXs），在原发性胰腺癌培养物和体内评估了一种具有联吡啶和三联吡啶配体以及一个配位不稳定位置的钌配合物（Ru1）的安全性和抗CSC活性。通过RNAseq分析以及线粒体特异性分子检测来确定其作用机制。

结果

我们表明Ru1能够在体外抑制CSCs的氧化磷酸化功能，更重要的是，它在大量人类胰腺PDXs以及结直肠癌和骨肉瘤PDXs中表现出优异的抗癌活性，且毒性低。机制研究表明，这种活性源于Ru1与CSCs线粒体DNA的D环区域结合，抑制与氧化磷酸化复合物相关的转录，导致线粒体氧消耗、膜电位和ATP生成减少，而所有这些对于严重依赖线粒体呼吸的CSCs来说都是必需的。

结论

总体而言，配位复合物Ru1不仅是一种令人兴奋的新型抗癌药物，也是一种剖析氧化磷酸化在CSCs中作用的分子工具。结果表明该化合物在体内安全、无毒且高效，这非常令人兴奋，使我们能够揭示基于靶向CSCs氧化磷酸化来对抗不同癌症类型前所未有的机制可能性。