Antitumour Activity of Dinitrosyl Iron Complexes with Thiol-Containing Ligands in Animals: An Overview

Review Article

Austin J Anal Pharm Chem. 2018; 5(3): 1104.

Antitumour Activity of Dinitrosyl Iron Complexes with Thiol-Containing Ligands in Animals: An Overview

Vanin AF1,2*, Ostrovskaya LA2 and Korman DB3

¹N.N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow, Russia

²Institute of Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

³N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia

*Corresponding author: Anatoly F Vanin, N.N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Institute of Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

Received: July 25, 2018; Accepted: September 12, 2018; Published: September 19, 2018


The data reviewed herein strongly suggest that binuclear dinitrosyl iron complexes (DNIC) with glutathione can fully (by 100%) suppress the growth of rapidly proliferating nonmalignant endometrial tumours in rats with experimental endometriosis, on the one hand, and retard the growth of transplanted malignant solid tumours (Lewis lung carcinoma), on the other hand. An inverse correlation was established between the antitumour effect of DNIC with glutathione on Lewis carcinoma and the mode of DNIC administration (intraperitoneal or intravenous). In the former case, the maximum inhibition of tumour growth was achieved by treatment of animals with the highest (200μmoles/kg) dose of DNIC, while after intravenous administration the inhibiting effect of DNIC increased with a decrease of the drug dose to 2μmoles/kg. It was suggested that Lewis carcinoma cells respond to DNIC used as a nitric monoxide (NO) donor by the development of a system of antinitrosative protection similar to that formed in many bacterial species in response to treatment with NO or its derivatives. It is not excluded that DNIC with thiol-containing ligands can fully suppress tumour growth when used as a nitrosonium (NO+) ion (but not NO) donor, as could be evidenced from the results of recent studies by Prof. Liaw et al. [Inorg. Chem. 2016, 55, 9383].

Keywords: Dinitrosyl iron complexes; Nitric oxide; Cancer; Experimental endometriosis; Apoptosis


AAF: 2-acetylaminofluorine; B- or M-DNIC: Binuclear or Mononuclear Dinitrosyl Iron Complexes; EDTA: Disodium Ethylenediaminetetraacetate; EMT: Endometrial Tumour; EPR: Electron Paramagnetic Resonance; GSH: Glutathione; GS-NO: S-nitrosoglutathione; MGD: N-methyl-D-glucamine Dithiocarbamate; MNIC-MGD: Mononitrosyl Iron Complexes with MGD.


The discovery of the unique capability of nitric monoxide (NO), the simplest chemical compound produced from L-arginine by enzymatic route, to exert beneficial (regulatory) effects on an immense diversity of metabolic processes occurring in human and animal organisms and its role of a key effector of cell-mediated immunity has opened up an outstanding opportunity for a detailed study of mechanisms of cytotoxic effects of NO with the main emphasis on the development, on its basis, of a vast array of potent new-generation drugs able to suppress the growth and proliferation of malignant tumours [1-6].

However, despite considerable efforts in this area [7-18], these expectations are not yet realized, and no major breakthrough has come about. By now, it has been established that in animal organisms NO can initiate both death and enhanced proliferation of normal and malignantly transformed cells and tissues. These effects are manifested at high (hundreds of micromoles and higher) concentrations of NO, while at low (micromolar) concentrations NO enhances tumour growth. This circumstance seems to be the main reason for the hitherto unsuccessful attempts of drug designers to develop, on the basis of NO, highly effective medicinal drugs able to exert potent and, which is even more important, irreversible inhibiting effects on tumour growth in animals.

Besides, it is still unclear whether NO synthesized from L-arginine by enzymatic route is present in animal tissues in the free form or as a constituent of chemical compounds responsible for its stabilization, transfer to biological targets and evacuation from the organism.

The aim of the present review is to demonstrate, on the basis of experimental evidence obtained thus far, that dinitrosyl iron complexes (DNIC) with thiol-containing (RS-) ligands including natural thiols (glutathione and L-cysteine) hold considerable promise as candidate medicinal drugs endowed with a unique capability to influence both normal and malignantly transformed cells and tissues.

Previous studies have shown that in animal cells DNIC are formed in the presence of endogenous and exogenous NO and are represented predominantly by the binuclear (diamagnetic) form (B-DNIC) with the chemical formula [(RS-)2Fe2 +(NO+)4]. In living organisms, the binuclear form of DNIC occurs in parallel with the mononuclear (paramagnetic) form (?-DNIC), which has the formula [(RS-)2Fe+(NO+)2] and is EPR-detectable [19-27].

Both forms of DNIC with thiol-containing ligands play the role of donors of NO and nitrosonium ions (NO+) [21-27]. Their interaction with heme- and thiol-containing proteins gives nitrosyl heme-containing complexes and S-nitrosothiols, respectively. The biological activity of heme- and thiol-containing proteins increases or decreases under the action of NO and NO+, which determines the overall effect of DNIC on physiological and biochemical processes occurring in animal organisms. It is by this mechanism that DNIC exert a dual effect one of which is beneficial (regulatory) and the other one is deleterious (cytotoxic). At low (1-2 μmol?s/kg) doses, DNIC produce a beneficial effect, while at higher (=150-200 μmoles/kg) doses it is the cytotoxic effect that comes to the foreground [25].

The novel therapeutic drug “Oxacom” in which DNIC with glutathione were used as the active substance was designed recently by a group of researchers at the Russian Cardiology Researchand- Production Complex [28]. The drug successfully underwent pharmacological testing. Its lethal i/v dose (LD50) for mice and rats was found to be equal to ~140 and 130 μmoles of B-DNIC/kg, respectively (as calculated per one iron atom in B-DNIC). Oxacom had no appreciable effect on different cell populations of rabbit blood either upon single i/v administration or after long-term treatment of animals with the drug; mutagenic effects of the latter on bone marrow cells of mice and rats were also absent. Intraperitoneal treatment of pregnant rats (n = 20) with Oxacom (daily, for 1-19 days) did not influence the number and mass of newborn rats, nor did the drug induce any significant pathological changes in the latter. These data altogether testify to complete therapeutic safety of Oxacom on experimental animals.

The results of pharmacological testing of Oxacom, which demonstrated very low toxicity of the novel drug for experimental animals, prompted us the idea to examine its hypotensive effect in a clinical study on 14 healthy male volunteers (aged 21-45) having normal arterial pressure and no chronic diseases. Intravenous infusion of Oxacom (3-4 ml) at a dose corresponding to 0.2 μmoles of B-DNIC with glutathione per kg of body mass caused a significant (by ~ 20%) and fast (within 3-4 min) drop of systolic and diastolic pressure from 137±4 to 110±4 mm Hg and from 85±2 to 61±4 mm Hg, respectively. The dynamics of changes in mean arterial pressure (MAP) is shown in Figure 1. In the subsequent period, which varied from 6 to 9 h, both parameters remained at the steady-state (low) level. However, after wakening the patients’ blood pressure returned to the initial values [28].