Structural and Molecular Biology, Division of Biosciences, Faculty of Life Sciences, University College London, London WC1E 6BT, UK.
Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
Toxins (Basel). 2018 Jun 27;10(7):261. doi: 10.3390/toxins10070261.
Immunotoxins are being investigated as anti-cancer therapies and consist of a cytotoxic enzyme fused to a cancer targeting antibody. All currently used toxins function via the inhibition of protein synthesis, making them highly potent in both healthy and transformed cells. This non-specific cell killing mechanism causes dose-limiting side effects that can severely limit the potential of immunotoxin therapy. In this study, the recently characterised bacterial toxin Burkholderia lethal factor 1 (BLF1) is investigated as a possible alternative payload for targeted toxin therapy in the treatment of neuroblastoma. BLF1 inhibits translation initiation by inactivation of eukaryotic initiation translation factor 4A (eIF4A), a putative anti-cancer target that has been shown to regulate a number of oncogenic proteins at the translational level. We show that cellular delivery of BLF1 selectively induces apoptosis in neuroblastoma cells that display MYCN amplification but has little effect on non-transformed cells. Future immunotoxins based on this enzyme may therefore have higher specificity towards MYCN-amplified cancer cells than more conventional ribosome-inactivating proteins, leading to an increased therapeutic window and decreased side effects.
免疫毒素被作为抗癌疗法进行研究，由与癌症靶向抗体融合的细胞毒性酶组成。目前所有使用的毒素都通过抑制蛋白质合成起作用，这使得它们在健康细胞和转化细胞中都具有很高的效力。这种非特异性的细胞杀伤机制导致剂量限制的副作用，这可能严重限制免疫毒素治疗的潜力。在这项研究中，最近被描述的细菌毒素伯克霍尔德氏菌致死因子 1（BLF1）被研究作为针对神经母细胞瘤的靶向毒素治疗的可能的替代有效载荷。BLF1 通过使真核起始翻译因子 4A（eIF4A）失活来抑制翻译起始，eIF4A 是一种潜在的抗癌靶标，已被证明在翻译水平上调节多种致癌蛋白。我们表明，BLF1 的细胞内递送选择性地诱导 MYCN 扩增的神经母细胞瘤细胞凋亡，但对非转化细胞几乎没有影响。因此，基于这种酶的未来免疫毒素可能比更传统的核糖体失活蛋白对 MYCN 扩增的癌细胞具有更高的特异性，从而增加治疗窗口并减少副作用。
