Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Department of Urology, Antibody-Based Diagnostics and Therapies, Medical Center-University of Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany.
Toxins (Basel). 2020 Nov 28;12(12):753. doi: 10.3390/toxins12120753.
The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.
表皮生长因子受体 (EGFR) 已被发现是前列腺癌 (PCa) 细胞的一个有价值的靶点。然而，EGFR 抑制剂在接受 PCa 治疗的患者的临床研究中大多失败。因此，我们测试了靶向毒素 EGF-PE40 和 EGF-PE24mut，它们由天然配体 EGF 作为结合域和 PE40（天然毒素域 Exotoxin A）或 PE24mut（其免疫原性降低的变体）作为毒素域组成。这两种靶向毒素都在周质中表达，并在表达 EGFR 的 PCa 细胞中诱导蛋白质生物合成的抑制。发现浓度和时间依赖性杀伤 PCa 细胞，在 48 和 72 小时后根据诱导的细胞凋亡，IC 值在低纳摩尔或皮摩尔范围内。EGF-PE24mut 的毒性比 EGF-PE40 低约 11-120 倍。两种靶向毒素的细胞毒性比 EGFR 抑制剂厄洛替尼高 600 至 140,000 倍。由于其高特异性细胞毒性，基于 EGF 的靶向毒素 EGF-PE40 和 EGF-PE24mut 是未来治疗 PCa 的有前途的候选药物。
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