Burkholderia Lethal Factor 1, a Novel Anti-Cancer Toxin, Demonstrates Selective Cytotoxicity in MYCN-Amplified Neuroblastoma Cells
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
Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK
Authors to whom correspondence should be addressed.
Toxins 2018, 10(7), 261; https://doi.org/10.3390/toxins10070261
Received: 18 May 2018 / Revised: 15 June 2018 / Accepted: 20 June 2018 / Published: 27 June 2018
(This article belongs to the Special Issue Venom and Toxin as Targeted Therapy)
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.