School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
State Key Laboratory of Antibody Medicine and Targeted Therapy, Shanghai, China.
J Immunol Res. 2018 Nov 25;2018:1090287. doi: 10.1155/2018/1090287. eCollection 2018.
Previously, we developed a novel EGFR-targeted antibody (denoted as Pan), which has superior antitumor activity against EGFR-overexpressed tumors. However, it shows marginal effect on the growth of esophageal cancers. Therefore, the variable region of Pan was fused to a fragment of Pseudomonas exotoxin A (PE38) to create the immunotoxin, denoted as Ptoxin (PT). Results indicated that PT shows more effective antitumor activity as compared with Pan both on EGFR-overexpressed KYSE-450 and KYSE-150 esophageal cancer cells, especially on KYSE-450 cells. Moreover, treatment of PT induces regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the enhanced antitumor effects of PT. Data showed that PT was more potent in reducing the phosphorylation of EGFR and ERK1/2. More importantly, we for the first time found that PT was more effective than Pan in inducing ROS accumulation by suppression of the Nrf2-Keap1 antioxidant pathway, and then induced apoptosis in KYSE-450 esophageal cancer cells, which may partly explain the more sensitive response of KYSE-450 to PT treatment. To conclude, our study provides a promising therapeutic approach for immunotoxin-based esophageal cancer treatment.
此前，我们开发了一种新型的 EGFR 靶向抗体（表示为 Pan），它对 EGFR 过表达的肿瘤具有优异的抗肿瘤活性。然而，它对食管癌的生长显示出轻微的效果。因此，将 Pan 的可变区融合到假单胞菌外毒素 A（PE38）的片段中，创建了免疫毒素，称为 Ptoxin（PT）。结果表明，与 Pan 相比，PT 在 EGFR 过表达的 KYSE-450 和 KYSE-150 食管癌细胞上均表现出更有效的抗肿瘤活性，尤其是在 KYSE-450 细胞上。此外，PT 处理可诱导裸鼠中 KYSE-450 肿瘤异种移植物的消退。此外，我们研究了 PT 增强抗肿瘤作用的潜在机制。数据表明，PT 更能有效降低 EGFR 和 ERK1/2 的磷酸化。更重要的是，我们首次发现，PT 通过抑制 Nrf2-Keap1 抗氧化途径更有效地诱导 ROS 积累，然后诱导 KYSE-450 食管癌细胞凋亡，这可能部分解释了 KYSE-450 对 PT 治疗更敏感的原因。总之，我们的研究为基于免疫毒素的食管癌治疗提供了一种有前途的治疗方法。
