50% Inhibitory concentrations for PNCs in HeLa and H1299 cells; MTT assay, 24 h of exposure. *Evaluation of IC50 is limited by low solubility of complexes.
1. Introduction
Nitroxyl radicals (NRs), which are sometimes called "organic nitrogen oxides” exhibit a wide range of biological activities, e.g., hemodynamic effect, protection against ionizing radiation, suppression of oxidative stress in different types of pathology (Soule et al., 2007; Wilcox, 2010). Already in early studies of the simplest NRs, their antitumor activity was demonstrated on a model tumor, leukemia La (Konovalova et al., 1964) and their cytotoxicity was shown for HeLa cells (Klimek, 1966). Subsequent studies included: 1) in-depth studies of antitumor activity of simple NRs (TEMPOL, TEMPO), 2) trials of therapeutical efficiency of NRs used in combination with the clinically approved anticancer drugs, and 3) synthesis and studies of hybrid compounds with NRs covalently bound to anticancer pharmacophores. Recent studies have shown that simple nitroxyls affect the cell viability through a redox-mediated signaling and induce a multifactor cell death response, including oxidative damage, cell cycle arrest and apoptosis (Gariboldi et al., 1998; 2000; 2003; Suy et al., 2005).
Nitroxide TEMPOL potentiates the cytotoxicity of doxorubicin in the culture of tumor cells with multidrug resistance (Gariboldi et al., 2006), and reduces its cardiotoxicity in rats (Monti et al, 1996). Combinations of low doses of nitroxyl TEMPO and doxorubicin or mitoxantrone exhibit additive or synergistic cytotoxicity, depending on the type of the tumor cells (Suy et al., 2005). In experiments on mice, nitroxyls at low doses (0.25–10 mg/kg) were shown to decrease toxicity of anticancer drugs substantially (Konovalova et al., 1991).
A considerable amount of research has been carried out on hybrid compounds containing NRs linked covalently to an anticancer pharmacophore. Nitroxyl derivatives of (thio)phosphamides (Shapiro et al., 1971; Emanuel et al., 1976; Sosnovsky & Paul, 1984; Sosnovsky & Li, 1985a), cyclophosphamide (Tsui et al., 1982), actinomycin D (Sinha et al., 1979), ethylenimino triazines (Emanuel & Konovalova, 1992), nitrosoureas (Raikov et al., 1985; Sosnovsky & Li, 1985b; Emanuel et al., 1986; Sen', 1993), 5-fluorouracil (Emanuel et al., 1985; Sen' et al., 1989), daunorubicin (Emanuel et al., 1982) were synthesized and studied. In comparison with the parent compounds, nitroxyl derivatives of the cytostatic drugs possess lower overall toxicity in animal studies and higher values of the
Over the past 30 years, platinum complexes occupy leading positions among drugs for cancer chemotherapy. The antitumor activity of cisplatin (CP) was discovered in 1960s, and in 1978 it was approved for clinical use (Kelland, 2007). The subsequent search for improved cisplatin analogues resulted in introduction of carboplatin (1989) and oxaliplatin (2002) into clinical practice. About 15 other complexes, for various reasons, have been rejected in clinical trials. Currently, JM216 (satraplatin), picoplatin, and nanopolymer ProLindac, bearing the oxaliplatin moiety, are subject to clinical trials (Wheate et al., 2010) (Fig. 1).
Cisplatin and other bivalent platinum complexes are effective against a number of human tumors. They are used in almost half of the treatment regimes in combinations with other anticancer drugs (Wheate et al., 2010). Complexes of bivalent platinum are highly reactive and, therefore, they are highly toxic drugs. To avoid acute toxicity, cisplatin is administered by continuous infusion of a very dilute solution (Blokhin & Perevodchikova, 1984). Another disadvantage of cisplatin is a rapid development of tumor resistance to this drug (Koeberle et al., 2010).
Complexes of Pt(IV), being chemically more inert than Pt(II) complexes, are characterized by moderate toxicity, and are suitable for oral administration. Complexes like satraplatin can pass through the digestive tract where they are absorbed into the bloodstream. With the bloodstream they reach organs and tissues, interact with cellular targets, and thus provide an antitumor effect (Kelland, 1999). Complexes of Pt(IV) are prodrugs (drug precursors) that, after entering into the cell or on the way to it, are reduced to corresponding active Pt(II) derivatives causing cytotoxic effect. At the same time, Pt(IV) complexes are potent inhibitors of proliferation of tumor cells including those resistant to cisplatin. Recent advances in the study of anticancer platinum amino complexes are summarized in a number of reviews (Kelland, 2007; Wheate et al., 2010; Klein & Hambley, 2009; Koeberle et al., 2010; Bonetti et al., 2009).
This review focuses mainly on the authors’ data on synthesis and studies of new highly active platinum compounds with low toxicity,
2. Synthesis of PNCs
2.1. Pt(II) complexes
Most of platinum complexes with high antitumor activity are non-ionic compounds with the
To achieve good yields, diiodo complexes cis-[Pt(RNH2)2I2] were prepared in the first step of the synthesis. The diiodo complexes were then converted to the target complexes by exchange reaction via water soluble dinitrato complexes (Fig. 2) (Dhara, 1970).
Complexes with two bulky amino ligands, such as compounds
The formulae of complexes obtained are shown in Fig. 4 (Sen' et al., 1996, 1998, 2000). Two biradical complexes of type
2.2. Pt(IV) complexes
Complexes of Pt(IV) with mixed amino ligands can be obtained only by oxidation of the Pt(II) precursors. According to the published method (Giandomenico et al., 1995), the starting Pt(II) complexes 6 are oxidized with an excess of H2O2 under relatively harsh conditions (70 °C, ≥ 2 h). Under these conditions, the oxidation of Pt(II)-nitroxyl complexes leads to the formation of significant amount of by-products, probably as a result of oxidation of nitroxyl radical by Pt(IV) at elevated temperature. We found that catalytic amounts of salts of tungstic acid strongly accelerate the reaction so that preparative oxidation under mild conditions (0 – 20 °C) is limited only by the rate of dissolution of the starting complex and takes from 0.5 to 2.5 hours.
This significantly increases the reaction selectivity and the yield of the target products.
The method described allows one to introduce different amines and exchange the so-called leaving X-ligands at the step of preparation of Pt(II) complexes (Fig. 3) and incorporate various carboxylate ligands with the alkyl residue R' of different length at the final step (Fig. 5). Thus, we can obtain the amino complexes of Pt(IV), which differ in chemical activity, solubility in water and aqueous-lipid distribution. The formulae of Pt(IV) complexes are shown in Fig. 6.
The structure of PNCs was proved by elemental analysis and spectroscopic data (Sen' et al., 1996, 1998, 2000, 2003, 2006). For complexes
3. Interaction of PNCs with DNA
Reactivity of Pt(II) diamine complexes
For relatively easily hydrolyzable complexes, including cisplatin, the reaction proceeds through the path
It is known that cisplatin and its analogues bind mainly to the guanine and adenine bases of DNA with the formation of cross-links, thus perturbing the structure of DNA (Kelland, 2007; Wheate et al., 2010). Analysis of the EPR spectra of DNA modified with PNCs, together with hydrolytic determination of platinated DNA bases, showed (Shugalii et al., 1998) that complexes
This result can be explained by immobilization of the radical moiety in the major DNA groove for the complex
Exciting opportunities for the instrumental use of PNCs were shown by Dunham et al., 1998. An adduct of
The ability of complexes
Ordinates in Fig. 9 are the values of specific destabilization of the DNA duplex,
Tm=(Tm′ – Tm)/100r,
where
4. Cytotoxicity of PNCs in tumor cell cultures
A simplified mechanism of cytotoxic effect of cisplatin and its analogs includes the transport of the complexes into the cell, their activation by the hydrolysis of leaving ligands (Cl—, carboxylates), penetration into the nucleus, and formation of adducts with DNA (Kelland, 2007; Wheate et al., 2010). The DNA lesions are either repaired, or initiate a complex process of programmed cell death,
Nitroxyl radicals are antioxidants, which can react with active radicals not only stoichiometrically, but also act as catalysts of redox reactions and mimetics of enzymatic systems. For example, in aqueous medium they perform superoxide dismutation through the reduction of radical HO2• by nitroxyl radical and the oxidation of radical O2•─ by oxoammonium cation (Sen' et al., 1976, 2009; Goldstein et al., 2003) (Fig. 10).
Interestingly, the nitroxyl based catalysis of dismutation of HO2• radical, generated in organic compounds undergoing oxidation, is carried out by the pair of nitroxyl radical/hydroxylamine (Denisov, 1996) (Fig. 11) Thermodynamic data are presented in support of the latter mechanism in organic medium. The measured constants of forward and reverse reactions at 50 C are equal to 104 – 105 M–1 s–1 (Denisov, 1996). Existence of two mechanisms for different media is not excluded. It looks reasonable that in an aqueous medium the preferred process is an electron transfer followed by a thermodynamically favorable hydration of oxoammonium cation (Fig. 10), while in an organic medium more typical reactions are the redox processes involving a hydrogen atom transfer (Fig. 11). Therefore, in biphasic aqueous-organic systems present in biological objects, both mechanisms are possible.
Like other antioxidants, under certain conditions, nitroxyls may exhibit pro-oxidant activity. The structure and concentration of nitroxyls, the medium properties, and other hard-to- identify factors can determine their anti– or pro-oxidant effect. At submillimolar concentrations, nitroxyls, as a rule, exhibit antioxidant properties and protect cells from apoptosis (Wilcox, 2010). At millimolar concentrations, nitroxyls are cytotoxic toward cultured tumor cells (Gariboldi et al., 1998, 2000, 2003, 2006; Suy et al., 2005) and are active against model animal tumors (Konovalova et al., 1964; Suy et al., 2005). Nitroxyl radicals cause cell death both in the wild type and p53 mutant cells (Suy et al., 2005). The study of interplay of platinum and nitroxyl pharmacophores combined in one molecule is of interest also in connection with the recent discussions on application of antioxidants and redox-active agents in tumor chemotherapy (Seifried, 2003; Wondrak, 2009).
To elucidate the interaction between platinum and nitroxyl pharmacophores, we studied the effect of 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO) on the toxicity of cisplatin to HeLa cells. According to the published approach (Reynolds & Maurer, 2005; Chou, 2006), the dose-response relationships were determined for individual agents and their mixtures at a fixed concentrations ratio. These data were transformed into the combination index (CI) – dead cells fraction (
Cell line | IC50, µM | ||||||||||
Cis-platin | JM216 | ||||||||||
HeLa | 14.8 | 125 | 112 | 14.4 | "/>200* | 13.4 | 200 | 4.18 | 2.45 | 0.23 | 0.09 |
H1299 | 66.7 | "/>150* | "/>150* | 38.8 | "/>200* | 25.4 | 220 | 24.6 | 16.6 | 1.36 | 0.69 |
Data on the cytotoxicity of PNCs also reflects the antagonism of platinum and nitroxyl pharmacophores. Complexes of platinum (II)
The H1299 cells are less sensitive to platinum complexes. Unlike the HeLa cells, H1299 cells do not contain p53 protein because of mutations of p53 gene in both alleles (Mitsudomi et al., 1992). Since p53 protein plays a key role in the process of apoptosis in response to DNA damages (Vousden & Prives, 2009), the observed lower sensitivity of H1299 cells to platinum complexes compared to HeLa cells can be related to lack of p53 function.
Our further study was focused on complex
Cell death found in flow cytofluorimetry experiments was shown to be apoptotic. Both cisplatin and complex
As it was discussed above, cisplatin and its analogues form adducts with DNA that, when are not repaired, trigger the tumor suppressor protein p53 (Alderden et al., 2006; Kelland, 2007; Wheate et al., 2010). Unlike cisplatin, the
5. Antitumor activity of PNCs in animal experimental tumors
Data on cytotoxicity revealed from cell culture studies and antitumor activity observed in animal tumor models do not correlate for platinum complexes. A striking example of this phenomenon is carboplatin, the known antitumor chemotherapy drug possessing negligible cytotoxicity
5.1. Pt(II) complexes
Toxicity and biological activity of Pt(II) diamino complexes depend on the structure of both the carrier amino ligands and the leaving groups, the latter being replaced during metabolism and target binding (Ho et al., 2003). The biradical complexes
Complex | Single dose, mg∙kg–1 | ||
570 (0.94) | 190 | 106 (0) | |
500 (0.74) | 166 | 79(1) | |
380 (0.61) | 127 | 76 (0) | |
27 (0.061) | 6.8 | 237 (1) | |
15 (0.033) | 3.8 | 292 (2) | |
80 (0.18) | 16 | 189 (0) | |
11 (0.022) | – | – | |
50 (0.10) | 11 | 132 (0) | |
500 (0.95) | 133 | 202 (2) | |
45 (0.095) | 15 | 133 (0) | |
100 (0.180) | 34 | 247 (0) | |
27 (0.052) | 9 | 270 (4) | |
46 (0.080) | 7.5 | 220 (4) | |
4.5 (0.007) | 1.5 | 120 (1) | |
260 (0.38) | 87 | 290 (1) | |
Cisplatin | 12 (0.040) | 3.0 | 245(1) |
Complexes
5.2. Pt(IV) complexes
Toxicity of Pt(IV) complexes
An important feature of PNCs is found in comparative study of development of tumor resistance in leukemia P388 to complex
Interesting results were observed when PNCs and cisplatin were used in combination at low doses (1/10 to 1/20 of
Complexes
It is known that reduction potentials
6. Conclusion
Recent studies (Wondrak, 2009; DeNicola et al., 2011) show that modulation of the redox state of cancerous cells could provide a new approach to suppression of tumor growth. Effects of nitroxyl radicals on the redox processes in normal cells and their cytotoxicity in tumor cells are documented in many examples (Gariboldi et al., 2000; Suy et al., 2005; Wilcox, 2010). Presumably, nitroxyls may affect the tumor cell viability through a redox-mediated signaling, which ultimately activate apoptosis.
On the other hand, the influence of nitroxyl radical on activity of anticancer agent, when they are used in combination or are covalently linked in one molecule, appears to depend on local concentration of radicals. At low concentrations of nitroxyls, which corresponds to rather low therapeutic doses of hybrid compounds, radicals are likely to impair the oxidative stress caused by tumor process and an anticancer agent itself. Published data show that
The known active anticancer complexes like cisplatin, oxaliplatin, and satraplatin bear in their structure redox-inert amino ligands. We synthesized structurally close analogs, i.e., platinum-nitroxyl complexes, amino ligands of which hold a wide spectrum of redox activity and are able to modulate biological properties of the new compounds. Their physicochemical properties, interaction with DNA, cytotoxicity
Acknowledgement
This work was partly supported by the Russian Foundation for Basic Research (Project No. 09-03-01187).
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