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. 2023 Dec;28(8):767-775.
doi: 10.1007/s00775-023-02026-w. Epub 2023 Nov 14.

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

Mie Riisom  1 , Stuart J Morrow  1 , Caitlin D Herbert  2 , William D J Tremlett  1 , Jonathan W Astin  2 , Stephen M F Jamieson  3 , Christian G Hartinger  4
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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

Mie Riisom et al. J Biol Inorg Chem. 2023 Dec.

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.

Keywords: Cellular accumulation; Hydroxyquinoline; LA-ICP-MS; Pyridinecarbothioamide; Ru anticancer complexes; Zebrafish.

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