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Open Access Highly Accessed Research article

The bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1) provides long-term survival in a murine glioma model

Eleonora Vannini12, Anna Panighini1, Chiara Cerri1, Alessia Fabbri3, Simonetta Lisi2, Enrico Pracucci2, Nicola Benedetto4, Riccardo Vannozzi4, Carla Fiorentini3, Matteo Caleo1* and Mario Costa1

  • * Corresponding author: Matteo Caleo caleo@in.cnr.it

  • † Equal contributors

Author Affiliations

1 CNR Neuroscience Institute, Via Moruzzi 1, 56124 Pisa, Italy

2 Scuola Normale Superiore, Piazza Dei Cavalieri 7, 56100 Pisa, Italy

3 Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy

4 Neurochirurgia, Azienda Ospedaliero-Universitaria Pisana, Via Paradisa 2, 56100 Pisa, Italy

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BMC Cancer 2014, 14:449  doi:10.1186/1471-2407-14-449

Published: 18 June 2014

Abstract

Background

Glioblastomas are largely unresponsive to all available treatments and there is therefore an urgent need for novel therapeutics. Here we have probed the antineoplastic effects of a bacterial protein toxin, the cytotoxic necrotizing factor 1 (CNF1), in the syngenic GL261 glioma cell model. CNF1 produces a long-lasting activation of Rho GTPases, with consequent blockade of cytodieresis in proliferating cells and promotion of neuron health and plasticity.

Methods

We have tested the antiproliferative effects of CNF1 on GL261 cells and human glioma cells obtained from surgical specimens. For the in vivo experiments, we injected GL261 cells into the adult mouse visual cortex, and five days later we administered either a single intracerebral dose of CNF1 or vehicle. To compare CNF1 with a canonical antitumoral drug, we infused temozolomide (TMZ) via minipumps for 1 week in an additional animal group.

Results

In culture, CNF1 was very effective in blocking proliferation of GL261 cells, leading them to multinucleation, senescence and death within 15 days. CNF1 had a similar cytotoxic effect in primary human glioma cells. CNF1 also inhibited motility of GL261 cells in a scratch-wound migration assay. Low dose (2 nM) CNF1 and continuous TMZ infusion significantly prolonged animal survival (median survival 35 days vs. 28 days in vehicle controls). Remarkably, increasing CNF1 concentration to 80 nM resulted in a dramatic enhancement of survival with no obvious toxicity. Indeed, 57% of the CNF1-treated animals survived up to 60 days following GL261 glioma cell transplant.

Conclusions

The activation of Rho GTPases by CNF1 represents a novel potential therapeutic strategy for the treatment of central nervous system tumors.

Keywords:
Glioma; Mouse; Cerebral cortex; CNF1; Temozolomide