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Copper is an endogenous metal ion that has been studied to prepare a new antitumoral agent with less side-effects. Copper is involved as a cofactor in several enzymes, in ROS production, in the promotion of tumor progression, metastasis, and angiogenesis, and has been found at high levels in serum and tissues of several types of human cancers. Under these circumstances, two strategies are commonly followed in the development of novel anticancer Copper-based drugs: the sequestration of free Copper ions and the synthesis of Copper complexes that trigger cell death. The latter strategy has been followed in the last 40 years and many reviews have covered the anticancer properties of a broad spectrum of Copper complexes, showing that the activity of these compounds is often multi factored. In this work, we would like to focus on the anticancer properties of mixed Cu(II) complexes bearing substituted or unsubstituted 1,10-phenanthroline based ligands and different classes of inorganic and organic auxiliary ligands. For each metal complex, information regarding the tested cell lines and the mechanistic studies will be reported and discussed. The exerted action mechanisms were presented according to the auxiliary ligand/s, the metallic centers, and the increasing complexity of the compound structures.

The novel copper complex [Cu(phen)2(salubrinal)](ClO4)2 (C0SAL) has been synthesised and characterised. Copper(ii) is coordinated by salubrinal through the thionic group, as shown by the UV-Vis, IR, ESI-MS and tandem mass results, together with the theoretical calculations. The formed complex showed a DPPH radical scavenging ability higher than that of salubrinal alone. Studies on lipid oxidation inhibition showed that the C0SAL concentration, required to inhibit the enzyme, was lower than that of salubrinal. The inhibition of the enzyme could take place via allosteric modulation, as suggested by docking calculations. C0SAL showed a good cytotoxic activity on A2780 cells, 82 fold higher than that of the precursor salubrinal and 1.4 fold higher than that of [Cu(phen)2(H2O)](ClO4)2. Treatment with C0SAL in SKOV3 ovarian cancer cells induced expression of GRP-78 and DDIT3 regulators of ER-stress response. The cytotoxic effect of C0SAL was reverted in the presence of TUDCA, suggesting that C0SAL induces cell death through ER-stress. In A2780 cells treated with C0SAL γ-H2AX was accumulated, suggesting that DNA damage was also involved.

There is an ongoing need for the development of new cancer therapeutics that combine high cytotoxic efficiency with low side effects, and also override resistance to the first-line chemotherapeutics. Copper(ii)-phenanthroline complexes are promising compounds that were shown previously to induce an immediate cytotoxic response over a panel of tumor cell lines in vitro. The molecular mechanism, however, remained unresolved. In this work we performed a thorough study of the copper(ii)-phenanthroline complexes containing different imidazolidine-2-thione ligands in ovarian cancer cells, and revealed that these complexes induce endoplasmic reticulum (ER) stress and subsequently cell death mediated by the unfolded protein response. Alleviation of the ER-stress by tauroursodeoxycholic acid (TUDCA) attenuated the cytotoxic effects. In summary, we have identified a novel, ER-dependent, molecular mechanism mediating cytotoxic effects of copper(ii)-phenanthroline complexes.

A large number of cancers are treated with cisplatin (CDDP). However, its use is limited by drug resistance, which is often related to intracellular levels of thiol-containing molecules such as glutathione (GSH). The role of GSH in cisplatin-resistant cancer cells is still unclear. GSH may form adducts with CDDP which results in the deactivation of the drug, and, actually, a high intracellular level of GSH was observed in some cisplatin-resistant cancers. To overcome drug resistance, CDDP is often administered in combination with one or more drugs to exploit a possible synergistic effect. In previous studies, we observed that the sensitivity to CDDP of leukemic and ovarian cisplatin-resistant cancer cells was restored in the presence of [Cu(phen) 2 (H 2 O)](ClO 4 ) 2 (C0) (phen is 1,10-phenathroline). In order to clarify the possible interactions between GSH and CDDP, the reactivity and competitive reactions among CDDP, C0 and GSH in binary and ternary mixtures were studied. The investigation was extended also to [Cu(phen)(H 2 O) 2 (ClO 4 ) 2 ] (C10) and GSSG, the oxidized form of GSH. It was observed that CDDP was able to react with the studied copper complexes and with GSH or GSSG. However, in mixtures containing CDDP, GSH or GSSG and C0 or C10, only copper-glutathione complexes were detected, while no platinum-glutathione adducts were found., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cisplatin, cis-diammineplatinum(II) dichloride, is a metal complex used in clinical practice for the treatment of cancer. Despite its great efficacy, it causes adverse reactions and most patients develop a resistance to cisplatin. To overcome these issues, a multi-drug therapy was introduced as a modern approach to exploit the drug synergy. A synergistic effect had been previously found when testing binary combinations of cisplatin and three copper complexes in vitro, namely, Cu(phen)(OH2)2(OClO3)2, [Cu(phen)2(OH2)](ClO4)2 and [Cu(phen)2(H2dit)](ClO4)2,(phen=1,10-phenanthroline, H2dit=imidazolidine-2-thione), against the human acute T-lymphoblastic leukaemia cell line (CCRF-CEM). In this work [Cu(phen)2(OH2)](ClO4)2 was also tested in combination with cisplatin against cisplatin-resistant sublines of CCRF-CEM (CCRF-CEM-res) and ovarian (A2780-res) cancer cell lines. The tested combinations show a synergistic effect against both the types of resistant cells. The possibility that this effect was caused by the formation of new adducts was considered and mass spectra of solutions containing cisplatin and one of the three copper complexes at a time were measured using electrospray ionisation at atmospheric-pressure mass spectrometry (ESI-MS). A mixed complex was detected and its stoichiometry was assessed on the basis of the isotopic pattern and the results of tandem mass spectrometry experiments. The formed complex was found to be [Cu(phen)(OH)μ-(Cl)2Pt(NH3)(H2O)](+)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The cytotoxic properties of copper(II) complexes with 1,10-phenanthroline (phen) can be modified by substitution in the phen backbone. For this purpose, Cu(II) complexes with phen, 1,10-phenanthrolin-5,6-dione (phendione) and 1,10-phenanthrolin-5,6-diol (phendiol) have been synthesised and characterised. The crystal structure of [Cu(phendione)2(OH2)(OClO3)](ClO4) is discussed. The complex formation equilibria between Cu(II) and phen or phendione were studied by potentiometric measurements at 25 and 37°C in 0.1 M ionic strength (NaCl). The antitumour activity of the compounds has been tested in vitro against a panel of tumour (DU-145, HEP-G2, SK-MES-1, CCRF-CEM, CCRF-SB) and normal (CRL-7065) human cell lines. The studied compounds generally present an antiproliferative effect greater than that of cisplatin. The phen and phendione ligands present a similar antiproliferative effect against all the tested cells. Phendiol presents an antiproliferative effect 1.3 to 18 times greater than that of phen or phendione for leukemic, lung, prostatic and fibroblast cells, while it presents less activity towards hepatic cells. Complexes with two ligands are more cytotoxic towards all the tested cell lines than complexes with one ligand and are generally more cytotoxic than the ligand alone. Complexes [Cu(phendiol)2(OH2)](ClO4)2 and [Cu(phendione)2(OH2)(OClO3)](ClO4) appear to be the most active compounds for the treatment of SK-MES-1 and HEP-G2 cells, respectively, being at least 18 times more cytotoxic than cisplatin. The studied Cu(II) complexes are characterised by a strong DNA affinity and were found to interact with DNA mainly by groove binding or electrostatic interactions. The complexes appear to act on cells with a mechanism different from that of cisplatin., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The combination of two or more drugs using multidrug mixtures is a trend in the treatment of cancer. The goal is to search for a synergistic effect and thereby reduce the required dose and inhibit the development of resistance. An advanced model-free approach for data exploration and analysis, based on artificial neural networks (ANN) and experimental design is proposed to predict and quantify the synergism of drugs. The proposed method non-linearly correlates the concentrations of drugs with the cytotoxicity of the mixture, providing the possibility of choosing the optimal drug combination that gives the maximum synergism. The use of ANN allows for the prediction of the cytotoxicity of each combination of drugs in the chosen concentration interval. The method was validated by preparing and experimentally testing the combinations with the predicted highest synergistic effect. In all cases, the data predicted by the network were experimentally confirmed. The method was applied to several binary mixtures of cisplatin and [Cu(1,10-orthophenanthroline)2(H2O)](ClO4)2, Cu(1,10-orthophenanthroline)(H2O)2(ClO4)2 or [Cu(1,10-orthophenanthroline)2(imidazolidine-2-thione)](ClO4)2. The cytotoxicity of the two drugs, alone and in combination, was determined against human acute T-lymphoblastic leukemia cells (CCRF-CEM). For all systems, a synergistic effect was found for selected combinations., (© 2013 Elsevier B.V. All rights reserved.)

Cu(II) complexes with 1,10-orthophenanthroline (phen) show cytotoxic and antitumoral effects. To enhance and exploit these features, we studied complexes containing one or two phen units together with N,N'-substituted-imidazolidine-2-thione (L). We synthesized and structurally characterized the precursor molecule Cu(phen)(OH(2))(2)(OClO(3))(2), and determined the complex formation constants of [Cu(phen)(L)](2+). We studied the cytotoxic activity of [Cu(phen)(2)(L)](ClO(4))(2) versus human hematologic (CCRF-CEM and CCRF-SB) and solid tumor-derived cell lines (K-MES-1, DU-145). The cytotoxic activities, in the 1-3 μM range, show that our Cu(II)-complexes possess comparable inhibitory activities against both leukemia and carcinoma cells, unlike the majority of antineoplastic agents, usually more potent against hematologic cancer cells than against solid tumor cells. Because the free Cu(II) ion is reduced by glutathione (GSH), we studied the reactivity of our complexes with GSH, providing evidence that no redox reaction occurred under the chosen experimental conditions. Complex formation equilibria were present, studied by spectrophotometric titrations. The redox properties of the prepared compounds were also investigated by cyclic voltammetry, confirming that the mixed Cu(II) complexes were resistant to reduction., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The synthesis, crystal structures, physicochemical properties and complex formation constants of [Cu(phen)(2)(L)](ClO(4))(2) complexes, where phen is 1,10-ortho-phenanthroline and L is a series of substituted imidazolidine-2-thione, have been studied. Single crystal X-ray diffraction revealed a distorted trigonal-bipyramidal geometry for all the molecules. The complex formation constants were determined in nonaqueous media by spectrophotometric measurements. Testing copper(II) complexes in mouse neuroblastoma N2a cells persistently infected with the 22L strain of the scrapie prion protein (22L-N2a) resulted in high cytotoxicity but no antiprion activity at nontoxic doses., (Copyright © 2010 Elsevier Inc. All rights reserved.)