一种双卡宾金(I)-NHC 配合物克服了 A2780 和 W1 卵巢癌细胞中的顺铂耐药性，突出了 pERK 作为细胞凋亡的调节剂。
A biscarbene gold(I)-NHC-complex overcomes cisplatin-resistance in A2780 and W1 ovarian cancer cells highlighting pERK as regulator of apoptosis.
机构信息
Department of Pharmacy, University Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, 38106, Brunswick, Germany.
出版信息
Cancer Chemother Pharmacol. 2023 Jul;92(1):57-69. doi: 10.1007/s00280-023-04548-1. Epub 2023 Jun 5.
PURPOSE
Cisplatin resistance is the major obstacle in the clinical treatment of ovarian cancer patients. Molecular mechanisms of cisplatin resistance are multifaceted. Gold(I)-compounds, i.e. N-heterocyclic carbene-gold(I)-complexes (NHC-Au(I)) has been regarded as promising cytotoxic drug candidates. However, their potential to overcome cisplatin resistance has hardly been addressed yet. Here we investigated the activity of the gold(I) drug auranofin and the NHC-Au(I)-compound MC3 in W1CR and A2780cis cisplatin-resistant ovarian cancer cells.
METHODS
Cytotoxicity of auranofin and MC3 was detected by MTT assay, correlated with intracellular gold(I) content, analyzed by AAS, and with flow cytometric detection of the cell cycle. Insight into cellular redox balance was provided by fluorimetric ROS-formation assay and western blotting thioredoxin (Trx) and Nrf2. The role of ERK was elucidated by using the inhibitor SCH772984 and its impact on cytotoxicity upon co-treatment with cisplatin and Au(I)-compounds, respectively.
RESULTS
MC3 overcomes cisplatin resistance in A2780cis and W1CR, and auranofin in W1CR cells completely, which is neither reflected by intracellular gold levels nor cell cycle changes. Upregulated redox balance appears as a basis for resistance. W1CR cells possess higher Trx levels, whereas A2780cis cells display strong Nrf2 expression as anti-oxidative protection. Nevertheless, overcoming redox balance appears not primary mode of activity comparing cisplatin and gold(I)-compounds. pERK emerges as a critical component and thus a promising target for overcoming resistance, regulating apoptosis differently in response to either gold(I) or cisplatin in A2780 cells.
CONCLUSION
These data reflect the complexity of cisplatin resistance in cell models and emphasize NHC-Au(I)-complexes as prospective cytotoxic agents for further investigations in that respect.
目的
顺铂耐药是卵巢癌患者临床治疗的主要障碍。顺铂耐药的分子机制是多方面的。金（I）化合物，即 N-杂环卡宾-金（I）配合物（NHC-Au（I））已被认为是有前途的细胞毒性药物候选物。然而，它们克服顺铂耐药的潜力尚未得到解决。在这里，我们研究了金（I）药物金诺芬和 NHC-Au（I）配合物 MC3 在 W1CR 和 A2780cis 顺铂耐药卵巢癌细胞中的活性。
方法
通过 MTT 测定法检测金诺芬和 MC3 的细胞毒性，与细胞内金（I）含量相关，通过 AAS 分析，并通过流式细胞术检测细胞周期。通过荧光 ROS 形成测定法和 Western 印迹法检测硫氧还蛋白（Trx）和 Nrf2 来了解细胞内氧化还原平衡。通过使用抑制剂 SCH772984 阐明 ERK 的作用及其对分别与顺铂和金（I）配合物共同处理时的细胞毒性的影响。
结果
MC3 克服了 A2780cis 和 W1CR 中的顺铂耐药性，而金诺芬则完全克服了 W1CR 细胞中的耐药性，这既不反映细胞内金水平的变化，也不反映细胞周期的变化。上调的氧化还原平衡似乎是耐药的基础。W1CR 细胞具有更高的 Trx 水平，而 A2780cis 细胞则表现出强烈的 Nrf2 表达作为抗氧化保护。然而，与顺铂和金（I）配合物相比，克服氧化还原平衡似乎不是主要的作用模式。pERK 作为一个关键组成部分出现，因此是克服耐药性的一个有前途的靶点，在 A2780 细胞中对凋亡的反应方式不同，对金（I）或顺铂的反应方式不同。
结论
这些数据反映了细胞模型中顺铂耐药的复杂性，并强调 NHC-Au（I）配合物作为进一步研究的有前途的细胞毒性药物。
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