Danilo Migoni

[Pt(O,O′‐acac)(γ‐acac)(DMS)], a new Pt compound exerting fast cytotoxicity in MCF‐7 breast cancer cells via the mitochondrial apoptotic pathway

We showed previously that a new Pt complex containing an O,O′‐chelated acetylacetonate ligand (acac) and a dimethylsulphide in the Pt coordination sphere, [Pt(O,O′‐acac)(γ‐acac)(DMS)], induces apoptosis in HeLa cells. The objective of this study was to investigate the hypothesis that [Pt(O,O′‐acac)(γ‐acac)(DMS)] is also cytotoxic in a MCF‐7 breast cancer cell line relatively insensitive to cisplatin, and to gain a more detailed analysis of the cell death pathways.

Water-soluble organometallic analogues of oxaliplatin with cytotoxic and anticlonogenic activity.

that determine the antitumor activity of platinum complexes have been outlined, such as the neutrality of the compounds. 7] For this reason, the majority of cisplatin analogues that have been tested for anticancer activity are neutral compounds of the type cis-[PtA2X2] [8, 9] and cis-[PtA2X4], [10–13] in which A is an amine ligand, and X is an anionic leaving group. Moreover, it was found that the effectiveness of cisplatin and its analogues could be greatly improved by substituting the labile chlorido ligands with other leaving groups. This approach led to the development of second-generation platinum drugs such as carboplatin, cis-[diammine(1,1-cyclobutanedicarboxylato-O,O’)platinum(II)] and nedaplatin, cis-[diammineglycoloato-O,O’-platinum(II)] , which are now in clinical use. Members of a third generation of platinum-based drugs, characterized by replacement of both the ammonia carrier ligands and the chlorido leaving groups of cisplatin, are now undergoing clinical trials. Many such third-generation platinum drugs bear the (R,R)-1,2-diaminocyclohexane (R,R-chxn) carrier ligand, and a successful example is oxaliplatin, [Pt(R,R-chxn)(oxalatoO,O’)] (Figure 1), which was recently approved for clinical use. Importantly, oxaliplatin is currently the only clinically approved cisplatin analogue that has shown potential for use in cisplatin-resistant tumors under preclinical evaluations. The discovery of antitumor and/or mutagenic activity in cationic Pt complexes has resulted from the pursuit of pharmacological advantages by violating some of the classical structure–activity relationships of platinum-based drugs. This idea has recently gained strength, as favorable interactions between aquated cationic species and human organic cation transporters (hOCT) have demonstrated an improvement in the antitumor activity of cisplatin and oxaliplatin. In this context, our interest has been focused on the unstable cationic complexes of the type [PtCl(h-C2H4)(N N)] , in which N N is a dinitrogen ligand. In particular, we synthesized new cationic complexes of the type [PtCl(h-C2H4)(R,R-chxn)] + (1) (Figure 1) and [PtCl(h-C2H4)(S,S-chxn)] + (2), organometallic analogues of oxaliplatin and hOCT substrates, and determined their cytotoxicity in terms of potential antitumor activity. In aqueous solution, complexes 1 and 2 are readily hydrolyzed into well-known antitumor-active oxaliplatin metabolites (i.e. , [PtCl2(R,R-chxn)] (3), [PtCl(H2O)(R,R-chxn)] + (5), and [Pt(H2O)2(R,R-chxn)] + (7) ; Figure 1) or the corresponding enantiomers (i.e. , [PtCl2(S,S-chxn)] (4), [PtCl(H2O)(S,S-chxn)] + (6), and [Pt(H2O)2(S,S-chxn)] 2 + (8)). Compounds 1 and 2 were synthesized by a method similar to that previously reported by Maresca and co-workers by allowing the lithium derivative of Zeise’s salt, Li[PtCl3(h -C2H4)] , to react with the appropriate diamine in methanol at low temperature (0 8C). Under these conditions, all reactants are soluble in the reaction medium, and products 1 and 2 can be obtained as white precipitates and isolated in high yields (~90 %) within a few hours (~3 h). The H NMR spectra of the enantiomeric complexes 1 and 2 in D2O show coupled multiplets (COSY) in the range of 1.2–2.7 ppm. These are attributed to the aliphatic protons of the coordinated cyclohexanediamine. A sharp singlet at 4.71 ppm flanked by two satellites due to coupling with the Pt nucleus (J(Pt H) = 56 Hz) can be assigned to the h-olefin on the basis of the olefin H chemical shift range observed for analogous cationic compounds. 44–47] Moreover, the presence of only one signal for all the olefin protons at room temperature in D2O indicates that the rotation around the platinum–olefin bond is fast on the NMR time Figure 1. Comparison of the structures of cisplatin, oxaliplatin, and [PtCl(hC2H4)(R,R-chxn)] + (1), and the hydrolysis products formed from both 1 and oxaliplatin: [PtCl2(R,R-chxn)] (3), [PtCl(H2O)(R,R-chxn)] + (5), and [Pt(H2O)2(R,Rchxn)] + (7) ; the latter of which are responsible for the antitumor activity of oxaliplatin.

Developing Central Nervous System and Vulnerability to Platinum Compounds

Comparative studies on the effects of the platinum complexes in use or in clinical trials are carried out in order to discover differences in the neurotoxic potential and the reversibility of neurotoxicity. In this paper, we summarized the current literature on neurotoxicity and chemoresistance of cisplatin (cisPt) and discussed our recent efforts on the interference of cisPt and a new platinum compound [Pt(O,O′-acac)(γ-acac)(DMS)] (PtAcacDMS), with high specific reactivity with sulphur ligands instead of nucleobases as cisPt, on some crucial events of rat postnatal cerebellum development. The acute effects of drug treatments on cell proliferation and death in the external granular layer and granule cell migration and the late effects on the dendrite growth of Purkinje cells were evaluated. Together with the demonstrated antineoplastic effectiveness in vitro, compared with cisPt, data suggest a lower neurotoxicity of PtAcacDMS, in spite of its presence in the brain that involves considerations on the blood brain barrier permeability.

New water-soluble platinum(II) phenanthroline complexes tested as cisplatin analogues: First-time comparison of cytotoxic activity between analogous four- and five-coordinate species.

Four- and five-coordinate platinum(II) complexes, cis-[PtCl2(A2)] (1) and [PtCl2(A2)(eta2-ethylene)] (2) {A2 = 4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BPS (mixture of isomers) (a); 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BCS (mixture of isomers) (b)} have been synthesized and characterized by 1H, 13C, and 195Pt NMR spectroscopy. The stability and high water solubility of complexes 1a, 1b and 2b, due to the presence of the polar SO3- groups on the ligands skeleton, allowed to test their in vitro cytotoxicity on HeLa tumour cells in a wide range of drug concentration. At low and medium incubation doses (<200 microM) 1a, 1b and 2b all showed similar in vitro cytotoxicity, negligible or much lower with respect to cisplatin. At doses higher than 200 microM their activity increased and 1b, the most active among the new complexes, exhibited a cytotoxicity comparable, although still lower, with respect to cisplatin. GFAAS Platinum analytical data showed that the tested compounds 1a, 1b and 2b, although carrying sulfonate charged groups, may undergo cellular uptake, which, in the case of 1b and 2b, is even higher with respect to cisplatin. Furthermore, in the case of 1b and 2b it has been possible to compare, for the first time, the cytotoxic activity for square-planar four-coordinate and trigonal-bipyramidal five-coordinate platinum(II) complexes having the same carrier ligand. The tendency of the five-coordinate species 2b to give at longer incubation time similar cytotoxicity with respect to the square-planar compound 1b suggests a possible use of the trigonal-bipyramidal five-coordinate complexes as prodrugs.

Antitumor activity of [Pt( O,O’ -acac)( γ -acac)(DMS)] in mouse xenograft model of breast cancer

The higher and selective cytotoxicity of [Pt(O,O′-acac)(γ-acac)(DMS)] toward cancer cell in both immortalized cell lines and in breast cancer cells in primary cultures, stimulated a pre-clinical study so as to evaluate its therapeutic potential in vivo. The efficacy of [Pt(O,O′-acac)(γ-acac)(DMS)] was assessed using a xenograft model of breast cancer developed by injection of MCF-7 cells in the flank of BALB/c nude mice. Treatment of solid tumor-bearing mice with [Pt(O,O′-acac)(γ-acac)(DMS)] induced up to 50% reduction of tumor mass compared with an average 10% inhibition recorded in cisplatin-treated animals. Thus, chemotherapy with [Pt(O,O′-acac)(γ-acac)(DMS)] was much more effective than cisplatin. We also demonstrated enhanced in vivo pharmacokinetics, biodistribution and tolerability of [Pt(O,O′-acac)(γ-acac)(DMS)] when compared with cisplatin administered in Wistar rats. Pharmacokinetics studies with [Pt(O,O′-acac)(γ-acac)(DMS)] revealed prolonged Pt persistence in systemic blood circulation and decreased nefrotoxicity and hepatotoxicity, major target sites of cisplatin toxicity. Overall, [Pt(O,O′-acac)(γ-acac)(DMS)] turned out to be extremely promising in terms of greater in vivo anticancer activity, reduced nephrotoxicity and acute toxicity compared with cisplatin.

(1)H NMR metabolomic profiling of the blue crab (Callinectes sapidus) from the Adriatic Sea (SE Italy): A comparison with warty crab (Eriphia verrucosa), and edible crab (Cancer pagurus).

The metabolomic profile of blue crab (Callinectes sapidus) captured in the Acquatina lagoon (SE Italy) was compared to an autochthonous (Eriphia verrucosa) and to a commercial crab species (Cancer pagurus). Both lipid and aqueous extracts of raw claw muscle were analyzed by (1)H NMR spectroscopy and MVA (multivariate data analysis). Aqueous extracts were characterized by a higher inter-specific discriminating power compared to lipid fractions. Specifically, higher levels of glutamate, alanine and glycine characterized the aqueous extract of C. sapidus, while homarine, lactate, betaine and taurine characterized E. verrucosa and C. pagurus. On the other hand, only the signals of monounsaturated fatty acids distinguished the lipid profiles of the three crab species. These results support the commercial exploitation and the integration of the blue crab in human diet of European countries as an healthy and valuable seafood.

Comparative analysis of the proximate and elemental composition of the blue crab Callinectes sapidus, the warty crab Eriphia verrucosa, and the edible crab Cancer pagurus

The proximate composition and element contents of claw muscle tissue of Atlantic blue crabs (Callinectes sapidus) were compared with the native warty crab (Eriphia verrucosa) and the commercially edible crab (Cancer pagurus). The scope of the analysis was to profile the chemical characteristics and nutritive value of the three crab species. Elemental fingerprints showed significant inter-specific differences, whereas non-significant variations in the moisture and ash contents were observed. In the blue crab, protein content was significantly lower than in the other two species, while its carbon content resulted lower than that characterizing only the warty crab. Among micro-elements, Ba, Cr, Cu, Li, Mn, Ni, and Pb showed extremely low concentrations and negligible among-species differences. Significant inter-specific differences were observed for Na, Sr, V, Ba, Cd and Zn; in particular, cadmium and zinc were characterized in the blue crab by concentrations significantly lower than in the other two species. The analysis of the available literature on the three species indicated a general lack of comparable information on their elemental composition. The need to implement extended elemental fingerprinting techniques for shellfish quality assessment is discussed, in view of other complementary profiling methods such as NMR-based metabolomics.

Different apoptotic effects of [Pt(O,O′-acac)(γ-acac)(DMS)] and cisplatin on normal and cancerous human epithelial breast cells in primary culture

The aim of this study was to determine whether [platinum (Pt)(O,O′‐acetylacetonate (acac))(γ‐acac)(dimethylsulphide (DMS))] is differentially cytotoxic in normal and cancer cells, and to measure comparative levels of cytotoxicity compared with cisplatin in the same cells.

Using the DPSIR framework to identify factors influencing the quality of groundwater in Grecìa Salentina (Puglia, Italy)

The Driver-Pressure-State-Impact-Response (DPSIR) framework was applied in a central area of the Salento peninsula to identify environmental and human factors influencing the quality of groundwater and propose strategies for its preservation. In accordance with this approach, a set of indicators providing a simplified description of the various components of a complex environmental system, directly or indirectly related to groundwater quality, was selected to obtain information useful for the management of water resources. A total of 42 indicators were taken into account: 11 for the driving forces, 5 for pressures, 21 for states, 2 for impacts and 3 for responses. The chemical and microbiological characterisation of the deep aquifer in the territory of Grecìa Salentina highlighted a number of cases of contamination attributable to risk factors present in the area. The study enabled the formulation of (a) hypotheses regarding the causes of poor water quality, and (b) management strategies for resolving the negative aspects of the overall state of health of the aquifer.

Adsorption of the cis-[Pt(NH3)2(P2O7)]2 − (phosphaplatin) on hydroxyapatite nanocrystals as a smart way to selectively release activated cis-[Pt(NH3)2Cl2] (cisplatin) in tumor tissues

The relevant adsorption of cis-[Pt(NH3)2(P2O7)](2-) (phosphaplatin) on hydroxyapatite nanocrystals (nHAP) was observed and studied in water suspension. Phosphaplatin cytotoxicity, which is very low for HeLa, MCF-7 and HS-5 cell lines could be enhanced, reaching that of cisplatin, by interaction with solid nHAP. This effect stems from nHAP ability to catalyze the phosphaplatin hydrolysis, producing the same hydrolytic species responsible for cisplatin antitumor activity.