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In vitro and in vivo accumulation of the anticancer Ru complexes [RuII(cym)(HQ)Cl] and [RuII(cym)(PCA)Cl]Cl

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Abstract

The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes [RuII(cym)(HQ)Cl] 1 (cym = η6-p-cymene, HQ = 8-hydroxyquinoline) and [RuII(cym)(PCA)Cl]Cl 2 (PCA = N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl2 resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.

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Acknowledgements

M.R. thanks Knud Højgaards Fond, Dagmar Marshalls Fond, Christian og Ottilia Brorsons Rejselegat for yngre videnskabsmænd – og kvinder, Carl og Ellen Hertz’ legat til Dansk Læge- og Naturvidenskab, Viet-Jacobsen Fonden, Eva & Henry Frænkels Mindefond and Direktør Jacob Madsens og Hustru Olga Madsens Fond for financial support.

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Authors and Affiliations

  1. School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Mie Riisom, Stuart J. Morrow, William D. J. Tremlett & Christian G. Hartinger

  2. Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Caitlin D. Herbert & Jonathan W. Astin

  3. Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Stephen M. F. Jamieson

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Riisom, M., Morrow, S.J., Herbert, C.D. et al. In vitro and in vivo accumulation of the anticancer Ru complexes [RuII(cym)(HQ)Cl] and [RuII(cym)(PCA)Cl]Cl. J Biol Inorg Chem 28, 767–775 (2023). https://doi.org/10.1007/s00775-023-02026-w

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