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
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
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Nrf2 抑制剂 Brusatol 与曲妥珠单抗联合通过抑制 Nrf2/HO-1 和 HER2-AKT/ERK1/2 通路，在 HER2 阳性癌症中发挥协同抗肿瘤活性
DOI：
10.1155/2020/9867595
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发表时间：
2020-07-20
影响因子：
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通讯作者：
Ren, Feng
中科院分区：
文献类型：
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作者：
Yang, Yun;Tian, Ziyin;Ren, Feng
HER 2靶向抗体曲妥珠单抗已显示出治疗HER 2阳性乳腺癌和胃癌的有效性;然而，其反应有限。目前，Nrf 2已被认为是通过与其他增殖信号通路的串扰促进癌症进展和抗性的关键转录因子。Nrf 2抑制剂是一种新型的抗肿瘤药物，具有良好的抗肿瘤作用。在本研究中，我们首次报道了布鲁沙醇通过逆转HER 2阳性癌细胞中的Nrf 2/HO-1和HER 2-AKT/ERK 1/2信号通路而发挥生长抑制作用。更重要的是，我们发现布鲁沙醇协同增强曲妥珠单抗对HER 2阳性SK-OV-3和BT-474细胞的抗肿瘤活性，这可能归因于抑制Nrf 2/HO-1和HER 2-AKT/ERK 1/2信号通路。此外，在BT-474和SK-0 V-3肿瘤异种移植物中也观察到协同效应。此外，我们的研究结果表明，曲妥珠单抗显着增强布鲁沙托诱导的ROS积累和凋亡水平，这可以进一步解释协同效应。总之，该研究为探索Nrf 2抑制联合HER 2靶向曲妥珠单抗作为治疗HER 2阳性癌症的潜在临床治疗方案提供了新的见解。
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.