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1. Introduction

Chemotherapy is a systemic treatment proposed to patients suffering from cancer. It is often a complementary approach to surgery or radiotherapy. The discovery of platinum’s inhibitory effect on tumor cell growth in the 1960s ^[1] was a milestone for anticancer drug application in medicine ^[2]. Platinum (II) sets at the center of the squared planar structure of cisplatin and is coordinated with two chlorides and two ammonia molecules in a cis configuration. Cisplatin and its derivative drugs (carboplatin of second generation and oxaliplatin of third generation) are used worldwide in clinical applications and several other platinum analogs (lobaplatin, nedaplatin, and heptaplatin) are approved in several countries (Figure 1) [3,4]^[3][4]. However, serious side effects including toxicities on the kidney, heart, ear, and liver, decrease in immunity, hemorrhage, and gastrointestinal disorders limit the use of platinum derivatives [5–7]^[5][6][7]. The appearance of drug resistances, issuing from acquired or intrinsic multiple genetic and epigenetic changes, has also limited the clinical use of platinum-derived drugs ^[8]. Platinum-based treatment efficiency is challenged by cross-resistance and multiple changes including a decreased accumulation of the drug, a reduction in DNA–drug adducts, a modification in cell survival gene expression, an alteration of DNA damage repair mechanisms, modifications of transporters, protein trafficking, and altered cell metabolism [9–14]^{[9][10][11][12][13][14]}.

Figure 1. Platinum (II) complexes.

To circumvent drug resistance, a possible approach consists of designing and developing new therapeutic metal-based anticancer drugs [15–21]^{[15][16][17][18][19][20][21]}. Several transition metals from the d-block of the periodic table (groups 3 to 12) and particularly essential trace metals [15^[15][22][23],22,23], such as copper [24–29]^{[24][25][26][27][28][29]}, are useful for the implementation of metal-based complexes in anticancer therapies. Copper plays central roles in various cellular processes being an essential micronutrient and an important cofactor for several metalloenzymes involved in mitochondrial metabolism (cytochrome c oxidase), or cellular radical detoxification against reactive oxygen species (ROS) (superoxide dismutase) ^[30]. Copper is essential for angiogenesis, proliferation, and migration of endothelial cells [31–33]^[31][32][33]. Elevated copper favors tumor growth and metastasis. It is detected in several brain ^[34], breast ^[35], colon, prostate ^[36], and lung ^[37] tumors and serves as an indicator of the course of the disease ^[38]. The differences in tumor cells’ responses to copper compared to normal cells laid the foundation of copper complexes’ (CuC) evolution as anticancer agents. Numerous developed CuC contain different sets of N, S, or O ligands and demonstrate high cytotoxicity and efficient antitumor activity ^[25]. Different mechanisms are involved in copper drugs’ anticancer effect. They act as chelators, and interact with and sequester endogenous copper, reducing its availability for tumor growth and angiogenesis ^[39]. On the contrary, ionophores trigger intracellular copper accumulation, cytotoxicity, and activate apoptosis inhibitor factor (XIAP) [24,40–46]^{[24][40][41][42][43][44][45][46]}. Other CuC are proteasome inhibitors [47,48]^[47][48]. Several CuC are actually on clinical trials: a number of copper/disulfiram-based drug combinations for therapy and as diagnostic tools (metastatic breast cancer and germ cell tumor), several casiopeínas compounds and elesclomol (leukemia), and thiosemicarbazone-based copper complexes labeled with a radioactive isotope for positron emission tomography imaging of hypoxia (in head and neck cancers) ^[49].

The cisplatin DNA-targeting principle of action also conditioned the development of anticancer copper-based drugs [4,23,50]^[4][23][50]. Antitumor activities of copper-based drugs are based on the interactive properties of both copper and the ligand. Copper toxicity results from its redox capacities (Cu(I) and Cu(II) redox states’ interconversion in oxidation–reduction cycles), the property to displace other ions from the enzyme binding sites, a high DNA binding affinity, and the ability to promote DNA breaks [28,51]^[28][51]. In most cases, copper modifies the backbone of the complexed ligand and grants better DNA affinity, specificity, and stability ^[52]. Copper derivatives can interact with DNA without the formation of covalent adducts. The noncovalent interactions with DNA include binding along with the major or the minor DNA grooves, intercalation, or electrostatic binding. Some copper-based drugs generate reactive oxygen species (ROS) that overwhelm cellular antioxidant defenses to produce oxidative damages in the cytoplasm, mitochondria, and DNA ^[53]. An important class of CuC, actually on focus for chemotherapy, inhibits topoisomerases (Top) 1 and 2, resulting in severe DNA damages, cell cycle arrest, and death [40,54–57]^{[40][54][55][56][57]}. Chemotherapeutics that target Top as poisons convert a transient DNA-enzyme complex into lethal DNA breaks [58–62]^{[58][59][60][61][62]}. However, topoisomerase inhibitors’ activity and their multifaceted binding modes to DNA, the effects, and the modulations they produce on the control of cancer cell division necessitate better understanding to optimize their efficiency.

2. Copper Complexes as Topoisomerases Inhibitors

DNA topoisomerases have been molecular targets for anticancer agents since their discovery in 1971 ^[63]. Topoisomerases regulate DNA winding and play essential functions in DNA replication and transcription [59,64]^[59][64]. Topoisomerase 1 (Top1) creates transient single-DNA nicks, while topoisomerases 2 (Top2α and Top2β) produce transient double-stranded DNA breaks. Both nuclear Top1 and Top2 are important targets for cancer chemotherapy, and Top inhibitors are used in therapeutic protocols [65–67]^[65][66][67]. Top inhibitors are classified into two groups: poisons and catalytic inhibitors. Top poisons (or interfacial poisons) stabilize the reversible cleavage complex formed between Top and DNA and form a ternary complex. Top2 catalytic inhibitors can prevent DNA strands cleavage through inhibition of the ATPase activity (novobiocin, merbarone), by impeding ATP hydrolysis to block Top dissociation from the DNA (ICRF-193), or by DNA intercalation at the Top fixation site (aclarubicinet) see ^[68]. In all cases, inhibitors convert the indispensable nuclear Top enzyme into a killing tool.

Top inhibitors’ activity increases upon complexation with copper ion. Top1, Top2, or Top1/2 inhibitors synthesized in the form of copper complexes (CuC) are mostly mononuclear Cu(II) complexes associated with a variety of ligands (Table 1). Different strategies are currently proposed to design and develop Top inhibitory agents based on ligands’ properties ^[69]. If both Top1 and Top2 inhibitors CuC primarily target DNA by a direct interaction through intercalation or cleavage, their antiproliferative activity is reinforced by ROS production and other molecular targets (Table 1) [25,52]^[25][52].

Table 1. Copper complexes inhibitors of topoisomerases: targeted top isoforms, cancer cell lines responses, and molecular mechanisms are summarized. * Tests were realized in vitro with human Top1 or Top2α/β unless specified. IC50: half-maximal inhibitory concentration. EC50: half-maximal effective concentration. GI50: half-average of growth inhibition.