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Nrf2 抑制剂 Brusatol 与曲妥珠单抗联合抑制 Nrf2/HO-1 和 HER2-AKT/ERK1/2 通路发挥协同抗肿瘤活性，用于治疗 HER2 阳性癌症。

Nrf2 Inhibitor, Brusatol in Combination with Trastuzumab Exerts Synergistic Antitumor Activity in HER2-Positive Cancers by Inhibiting Nrf2/HO-1 and HER2-AKT/ERK1/2 Pathways.

机构信息

School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.

Department of Experimental therapeutics, British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada.

出版信息

Oxid Med Cell Longev. 2020 Jul 19;2020:9867595. doi: 10.1155/2020/9867595. eCollection 2020.

DOI:10.1155/2020/9867595
PMID:32765809
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7387975/
Abstract

The HER2-targeting antibody trastuzumab has shown effectiveness in treating HER2-positive breast and gastric cancers; however, its responses are limited. Currently, Nrf2 has been deemed as a key transcription factor in promoting cancer progression and resistance by crosstalk with other proliferative signaling pathways. Brusatol as a novel Nrf2 inhibitor has been deemed as an efficacious and safe drug candidate in cancer therapy. In this study, we firstly reported that brusatol exerted the growth-inhibitory effects on HER2-positive cancer cells by regressing Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways in these cells. More importantly, we found that brusatol synergistically enhanced the antitumor activity of trastuzumab against HER2-positive SK-OV-3 and BT-474 cells, which may be attributed to the inhibition of Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways. Furthermore, the synergistic effects were also observed in BT-474 and SK-OV-3 tumor xenografts. In addition, our results showed that trastuzumab markedly enhanced brusatol-induced ROS accumulation and apoptosis level, which could further explain the synergistic effects. To conclude, the study provided a new insight on exploring Nrf2 inhibition in combination with HER2-targeted trastuzumab as a potential clinical treatment regimen in treating HER2-positive cancers.

摘要

曲妥珠单抗是一种针对 HER2 的抗体，已被证明对治疗 HER2 阳性乳腺癌和胃癌有效；然而，其疗效有限。目前，Nrf2 已被认为是通过与其他增殖信号通路相互作用促进癌症进展和耐药性的关键转录因子。作为一种新型的 Nrf2 抑制剂，布瑞佐菌素已被认为是癌症治疗中一种有效且安全的药物候选物。在本研究中，我们首先报道布瑞佐菌素通过下调这些细胞中的 Nrf2/HO-1 和 HER2-AKT/ERK1/2 信号通路，对 HER2 阳性癌细胞发挥生长抑制作用。更重要的是，我们发现布瑞佐菌素与曲妥珠单抗联合使用可协同增强曲妥珠单抗对 HER2 阳性 SK-OV-3 和 BT-474 细胞的抗肿瘤活性，这可能归因于 Nrf2/HO-1 和 HER2-AKT/ERK1/2 信号通路的抑制。此外，在 BT-474 和 SK-OV-3 肿瘤异种移植模型中也观察到了协同作用。此外，我们的结果表明，曲妥珠单抗显著增强了布瑞佐菌素诱导的 ROS 积累和凋亡水平，这可以进一步解释协同作用。总之，该研究为探索 Nrf2 抑制与曲妥珠单抗靶向 HER2 联合治疗 HER2 阳性癌症提供了新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/4f5ad745042f/OMCL2020-9867595.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/d487c54c7c70/OMCL2020-9867595.001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/5d73f8360f7c/OMCL2020-9867595.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/4f5ad745042f/OMCL2020-9867595.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/d487c54c7c70/OMCL2020-9867595.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/d1b825ae4c84/OMCL2020-9867595.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/43e37082d2dc/OMCL2020-9867595.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/cb36de0ff006/OMCL2020-9867595.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/35fc8616e370/OMCL2020-9867595.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/d9255fd5ec43/OMCL2020-9867595.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/5d73f8360f7c/OMCL2020-9867595.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebc/7387975/4f5ad745042f/OMCL2020-9867595.008.jpg

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