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Dual functionality of the antimicrobial agent taurolidine which demonstrates effective anti-tumor properties in pediatric neuroblastoma

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Summary

High-risk, relapsed and refractory neuroblastoma are associated with poor 5-years survival rates, demonstrating the need for investigational therapeutic agents to treat this disease. Taurolidine is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. Taurolidine has also demonstrated anti-neoplastic effects in a range of cancers, providing the rationale to investigate the activity of taurolidine against neuroblastoma in preclinical studies. We investigated the in vitro activity of taurolidine against neuroblastoma using the alamar blue cytotoxicity assay, phase-contrast light microscopy, western blotting and analysis of global gene expression by RNA-Seq. In vivo activity of taurolidine was evaluated using mouse xenograft models. In vitro pre-clinical data show that taurolidine is cytotoxic to neuroblastoma cell lines, inducing cell death by apoptosis. Analysis of global gene expression and determination of signaling pathway activation scores using the in silico Pathway Activation Network Decomposition Analysis (iPANDA) platform indicates that taurolidine has an effect on the Notch, mitogen-activated protein kinase (MAPK) and interleukin-10 (IL-10) signaling pathways. In vivo experiments in xenograft mouse models show that taurolidine decreases tumor growth and improves survival. These results provide supportive pre-clinical data on the activity of taurolidine against neuroblastoma. The findings support the rationale for further evaluation of taurolidine for the treatment of relapsed/refractory neuroblastoma patients in an early phase clinical trial.

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Acknowledgments

This research was supported by the POETIC Foundation (grant number 10014557) and CorMedix Inc. (grant number 10017362). We thank the Charbonneau Microscope Facility (University of Calgary) for support with phase-contrast microscopy.

Funding

This research was supported by the POETIC Foundation (grant number 10014557) and CorMedix Inc. (grant number 10017362).

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Authors and Affiliations

  1. POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary, Calgary, Alberta, Canada

    Lucy Swift, Chunfen Zhang & Aru Narendran

  2. Division of Pediatric Oncology, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada

    Lucy Swift, Chunfen Zhang & Aru Narendran

  3. Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada

    Olga Kovalchuk

  4. Phoenix Children’s Hospital, Center for Cancer and Blood Disorders, Phoenix, AZ, USA

    Jessica Boklan

  5. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Tanya Trippett

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  1. Lucy Swift
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Correspondence to Aru Narendran.

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L. Swift declares that she has no conflict of interest. C. Zhang declares that she has no conflict of interest. O. Kovalchuk declares that she has no conflict of interest. J. Boklan declares that she has no conflict of interest. T. Trippett declares that she has no conflict of interest. A. Narendran declares that he has no conflict of interest.

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All applicable international, national, and institutional guidelines for the care and use of animals were followed. All protocols were reviewed and approved by the Animal Care Committee of the University of Calgary (Protocol approval number: AC16–0243). This article does not contain any studies with human participants performed by any of the authors.

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Swift, L., Zhang, C., Kovalchuk, O. et al. Dual functionality of the antimicrobial agent taurolidine which demonstrates effective anti-tumor properties in pediatric neuroblastoma. Invest New Drugs 38, 690–699 (2020). https://doi.org/10.1007/s10637-019-00816-1

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