Ruthenium(II) and Platinum(II) Complexes with Biologically Active Aminoflavone Ligands Exhibit In Vitro Anticancer Activity.

Małgorzata Fabijańska,Maria M Kasprzak,Justyn Ochocki

doi:10.3390/ijms22147568

Małgorzata Fabijańska, Maria M Kasprzak + Show 1 more

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https://doi.org/10.3390/ijms22147568

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Abstract

Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of cis-dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), cis-dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and trans-dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described.

Highlights

Accepted: 12 July 2021Drug resistance remains one of the biggest challenges in cancer therapy
Our study has three main experimental parts: (1) we evaluated the properties of the biological material; (2) assessed the cytotoxicity of the ruthenium(II) and platinum(II) compounds with flavonoid bioligands previously obtained by our group (cis-dichlorobis(3-imino-2methoxyflavanone)ruthenium(II) (134) 2 [17], cis-dichlorobis(3-imino-2-ethoxyflavanone) ruthenium(II) (138) 3 [17], and trans-dichlorobis(3-aminoflavone)platinum(II) (TCAP)4 [18], with cis-diaminadichloroplatinum(II) (CDDP or cisplatin) 1—an anticancer drug—used as a reference compound), studying the mechanism of action of the tested
Elevated level of glutathione is commonly found in cisplatin-resistant cancer cells [1], as a crucial pre-target resistance mechanism. It can be a cause of cellular cross resistance to other cytostatic agents, especially metal-based ones, and those acting by oxidative stress in cancer cells

Summary

Introduction

Accepted: 12 July 2021Drug resistance remains one of the biggest challenges in cancer therapy. As cisplatin has been found to be the major therapeutic options in some clinical situations, the development of innovative strategies that overcome drug resistance constitutes a goal with important clinical implications [1]. Over the last 40 years, large numbers of platinum-metal compounds with anticancer activity have been synthesized, such as mono- and multi-nuclear platinum complexes, trans-platinum complexes, Pt(IV) complexes, and other synthesis strategies. The outcomes of clinical trials of these complexes resembled the classical platinum complexes and none of the non-classical platinum complexes has been approved for clinical application. This phenomenon has encouraged many scientists to be engaged in designing novel platinum complexes [2].

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