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    In-vivo evaluation of the response of Galleria mellonella larvae to novel copper(II) phenanthroline-phenazine complexes


    Rochford, Garret and Molphy, Zara and Browne, Niall and Surlis, Carla and Devereux, Michael and McCann, Malachy and Kellett, Andrew and Howe, Orla and Kavanagh, Kevin (2018) In-vivo evaluation of the response of Galleria mellonella larvae to novel copper(II) phenanthroline-phenazine complexes. Journal of Inorganic Biochemistry, 186. pp. 135-146. ISSN 0162-0134

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    Abstract

    Herein we report the in-vivo characterisation and metabolic changes in Galleria mellonella larvae to a series of bischelate copper(II) phenanthroline-phenazine cationic complexes of [Cu(phen)2] 2+ (Cu-Phen), [Cu(DPQ) (Phen)]2+ (Cu-DPQ-Phen) and [Cu(DPPZ)(Phen)]2+ (Cu-DPPZ-Phen) (where phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-ƒ:2′,3′-h]quinoxaline and DPPZ = dipyrido[3,2-a:2′,3′-c]phenazine). Our aim was to investigate the influence of the systematic extension of the ligated phenazine ligand in the G. mellonella model as a first step towards assessing the in-vivo tolerance and mode of action of the complex series with respect to the well-studied oxidative chemical nuclease, Cu-Phen. The Lethal Dose50 (LD50) values were established over dose ranges of 2 – 30 μg at 4-, 24-, 48- and 72 h by mortality assessment, with Cu-Phen eliciting the highest mortality at 4 h (Cu-Phen, 12.62 μg < Cu-DPQ-Phen, 21.53 μg < Cu-DPPZ-Phen, 26.07 μg). At other timepoints, a similar profile was observed as the phenazine π-backbone within the complex scaffold was extended. Assessment of both cellular response and related gene expression demonstrated that the complexes did not initiate an immune response. However, Label-Free Quantification proteomic data indicated the larval response was associated with upregulation of key proteins such as Glutathione S-transferase, purine synthesis and glycolysis/gluconeogenesis (e.g. fructose-bisphosphate aldolase and glyceraldehyde-3-phosphate). Both Cu-Phen and Cu-DPQ-Phen elicited a similar in-vivo response in contrast to Cu-DPPZ-Phen, which displayed a substantial increase in nitrogen detoxification proteins and proteins with calcium binding sites. Overall, the response of G. mellonella larvae exposure to the complex series is dominated by detoxification and metabolic proteome response mechanisms.

    Item Type: Article
    Keywords: Chemical nuclease; Copper phenanthrene; Galleria mellonella; in-vivo toxicity; DNA; LFQ proteomics;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12442
    Identification Number: https://doi.org/10.1016/j.jinorgbio.2018.05.020
    Depositing User: Dr. Kevin Kavanagh
    Date Deposited: 17 Feb 2020 17:05
    Journal or Publication Title: Journal of Inorganic Biochemistry
    Publisher: Elsevier
    Refereed: Yes
    URI:

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