Dinitrosyl Iron Complexes with Glutathione Suppress Surgically Induced Experimental Endometriosis in Rats

Abstract

The review describes the results of our most recent investigations into miscellaneous effects of Dinitrosyl Iron Complexes (DNIC) with Glutathione and S-Nitrosoglutathione (GS-NO) as donors of Nitric Monoxide (NO) on the development of surgically induced endometriosis in rats. Whereas DNIC induced selective suppression of the growth of endometrioid tumors in implantation niduses, GS-NO enhanced tumour growth and lowered the immune responsiveness of experimental rats. It was suggested that the selective cytotoxic action of DNIC with glutathione on endometrioid tumors is a result of DNIC decomposition by endogenous iron chelators generated by tumor cells in order to provide the latter with iron required for fast tumor growth. The nitric monoxide released from DNIC either inside tumor cells or in their vicinity is oxidized to cytotoxic peroxynitrite and thus contributes to the strictly selective cytotoxic effect of DNIC on tumor cells. Such selectivity is not specific to GS-NO whose decomposition is spontaneous and can take place in different divisions of the abdominal cavity.

Keywords: Dinitrosyl iron complexes; Nitric oxide; S-Nitrosothiols; Endometriosis

Abbreviations

B-M-DNIC: Binuclear or Mononuclear Dinitrosyl Iron Complexes; EMT: Endometrioid Tumors; EPR: Electron Paramagnetic Resonance; GS-NO: S-nitrosoglutathione; MNICDETC: Mononitrosyl Iron Complexes with Diethyldithiocarbamate; RCRPC: Russian Cardiological Research-and-Production Complex; RS-NO: S-Nitosothiol

Introduction

Previous studies carried out by the members of our research team at the Semenov Institute of Chemical Physics of the Russian Academy of Sciences have established that exogenous water-soluble Dinitrosyl Iron Complexes (DNIC) with glutathione as Nitric Monoxide donors (NO) can selectively suppress the development of experimental endometriosis in rats induced by surgical transplantation of two 2-mm fragments of uterine tissue onto the inner surface of the abdominal wall [1-3]. This effect is manifested in early and more advanced steps of tumor growth. Another NO donor, viz., S-nitrosoglutathione, exerts a non-selective suppressive effect (if any) on tumor growth, which is directed against both endometrioid tumours and other tissues. By weakening the immune responsiveness in experimental animals, S-nitrosoglutathione drastically enhances tumor growth in some of them. This paper is an overview of the results of our studies into miscellaneous effects of DNIC with glutathione on the development of surgically induced experimental endometriosis in rats. It was established that the selectivity of cytotoxic effects of DNIC on endometrioid tumors is determined by their physico-chemical characteristics and the ability to undergo decomposition inside or in the vicinity of endometrioid tumours with a release of considerable amounts of NO.

Dinitrosyl Iron Complexes with Glutathione Represent a “Working Form” of Nitric Monoxide (NO), One of the Most Universal Regulators of Biological Processes

It has been established that Nitric Monoxide (NO), one of the simplest chemical compounds synthesized from L-arginine by the enzymatic route in the presence of three isoforms of NO-Synthesis (NOS), functions as one of the most universal regulators of an immense variety of biological processes occurring in human and animal organisms [4]. This activity is usually manifested at micro molar steady-state concentrations of NO synthesized by constitutive isoforms of NOS, viz., the endothelial (eNOS) and neuronal (n-NOS) is forms [1]. At steady-state concentrations of NO ≥100 μM generated by inducible NOS (iNOS), NO molecules, or, more specifically, the product of their interaction with the superoxide, viz., Peroxynitrite (ONOO-) exerts various cytotoxic effects on cells and tissues by acting as a potent effector of cell-mediated immunity [4-6]. At physiological рН, the protonation of peroxynitrite gives a hydroxyl radical and nitrogen dioxide; both products are responsible for the cytotoxic effect of peroxynitrite [4,5]. Being free-radical compounds, NO and superoxide anions easily interact with each other by the diffusioncontrolled mechanism resulting in a fast decrease of the NO content in cells and tissues. To prevent the NO decrease, the Nature utilizes the ability of NO to initiate the reversible formation in biological systems of endogenous nitroso derivatives, viz., S-Nitrosothiols (RSNO) and Dinitrosyl Iron Complexes (DNIC) with thiol-containing ligands [7-9], which are responsible for stabilization, deposition, migration and transfer of NO to its biological targets. DNIC with thiol-containing ligands, which are easily synthesized by the chemical route, exist in both paramagnetic, EPR-active mononuclear (М-DNIC) and diamagnetic, EPR-silent binuclear (B-DNIC) forms; their chemical formulas appear as {(RS-)₂ Fe(NO)₂} and {(RS-)₂ Fe₂(NO)₄}, respectively [10-13]. B-DNIC represent thioethers of thiolcontaining compounds (e.g, glutathione or cysteine) and Roussins’s red salt (chemical formula {(S)2 Fe₂(NO)₄}) [10]. The concentration of М- and B-DNIC with thiol-containing ligands is determined by the chemical equilibrium shown in (Scheme 1):

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