4. Vanadium Complexed with Marketed-Approved Drugs
Vanadium-based complexes may incorporate different ligands, ranging from chemical elements such as cobalt to plant pigments (flavonoids)
[37][38], or synthetic drugs, enclosing defined pharmacological properties and indications
[39]. Complexes of metal ions with free drugs may reduce the toxicity of the drugs and increase their lipophilicity, improving their transport across cell membranes
[40]. Here, the effects of several vanadium compounds and complexes with distinct chemical structures are described (
Figure 1).
Figure 1. Structures of vanadium compounds and complexes with approved drugs. (
A) Structure of the decameric species of vanadate, decavanadate, V
10O
286-. Color code: V, gray; O, red. The green (four), blue (four), and brown (two) circles refer to vanadium atoms with the same chemical environment
[41]; (
B) Ball and stick representation of metforminium decavanadate (H
2Metf)
3[V
10O
28]·8H
2O. Water molecules are omitted for clarity
[42]; (
C) Polyhedral representation common to the Mo
6L
2 (where L corresponds to a ligand, either alendronate (Ale) or zoledronate (Zol)) POM frameworks, green tetrahedral = PO
3C, orange polyhedra = MoO
6 [43]; (
D) Oxidovanadium(IV) complexes with cetirizine, [VO(CTZ)
2] 2H
2O
[44]; (
E) Clotrimazole oxidovanadium(IV) complex [VO(SO
4)(CTNZ)(H
2O)]H
2O; (
F) Miconazole oxidovanadium(IV) complex, [VO(SO
4)(MNZ)
2] H
2O; (
G) Pantoprazole oxidovanadium(IV) complex, [VO(PNZ)
2]SO
4.2H
2O; (
H) Oxidovanadium(IV) complexes with Schift based compounds, such as for ibuprofen and naproxen
[45]; (
I) Oxidovanadium(IV) chrysin complex
[46].
4.1. Vanadyl(IV) Complexes with Non-Steroidal Anti-Inflammatory Drugs
Tumor-promoting inflammation is one of the hallmarks of cancers, along with many others, such as avoiding immune destruction
[47]. The connection of inflammation with tumor development and progression may justify the interest in exploring anti-inflammatory drugs in cancer research. Studies regarding their repurposing have shown their potential as chemopreventive agents against certain types of cancer or as anticancer agents
[48]. In fact, non-steroidal anti-inflammatory drugs (NSAIDs) may protect against the development of cancer, as studied for aspirin and ibuprofen at low doses
[49].
Notably, such NSAIDs have a carboxylate group available for metal–ligand interaction, which has raised interest in their use in complexes with vanadium for medicinal applications
[50]. Different vanadyl(IV) complexes with either ibuprofen (2-(4-isobutylphenyl)propionic acid) ([VO(Ibu)
2].5CH
3OH) or naproxen (6-methoxy-α-methyl-2-naphthalene acetic acid) ([VO(Nap)
2].5CH
3OH) have been synthesized
[51]. All NSAIDs–VO
2+ complexes (
Figure 1H) were then characterized with respect to their potential effect on the proliferation of osteoblast-like cells
[51]. The results of the mitogenic bioassay with increasing concentrations of NSAIDs-VO
2+, in both tumoral UMR106 from a rat osteosarcoma (
Figure 2A) and non-transformed MC3T3E1 derived from mouse calvaria (
Figure 2B), showed in some cases a biphasic effect (Ibu-VO and Nap-VO in UMR106), or the inhibition of cell growth in a dose–response manner (Nap-VO in MC3T3E1 cells and UMR106 cells in high doses) (
Figure 2). From all tested compounds, Nap-VO was the most potent inhibitor of cell growth, mainly in osteosarcoma cells (
Figure 2A), as subsequently confirmed by the same research group
[52]. By contrast, ibuprofen and naproxen alone, tested in the same concentration range of 0–100 µM, neither inhibited nor promoted cell proliferation.
Figure 2. Effects of Ibu-VO, Nap-VO, and VO, on UMR106 (
A) and MC3T3E1 (
B) cell proliferation. Approximate values were extracted from
[51] and are expressed as a percentage of the basal value (without treatment, 0 µM). Abbreviations: Ibu-VO, vanadyl(IV) complexes with ibuprofen; Nap-VO, vanadyl(IV) complexes with naproxen; VO, vanadyl(IV).
In the case of the vanadyl(IV)–aspirin complex (Asp-VO), the non-transformed cell line was found to be more sensitive to such derivatives when compared with the osteosarcoma cell line
[53]. Nevertheless, a follow-up study showed that Asp-VO was able to inhibit cell adhesion, spreading, and migration in UMR106 cells, in a mechanism dependent on protein kinase A (PKA) activity
[54]. Taken together, these results highlight the need for investigating the anticarcinogenic potential of NSAIDs–VO
2+ complexes in other types of tumors.
4.2. Vanadium Compounds Bound to Bisphosphonates
Bisphosphonates (BPs) are used to treat bone resorption. Both alendronate (Ale) and zoledronate (Zol) are classed as nitrogen-containing BPs. BPs can induce apoptosis, due to the production of cytotoxic ATP analogs
[55][56]. In addition, BPs can inhibit cell adhesion, invasion, and proliferation; modulate the immune system, and affect angiogenesis
[57]. Because of its high affinity for bone, Zol is used in the treatment of metastatic prostate bone metastases
[58][59][60]. BPs also reduce bone metastasis and mortality in patients with early-stage breast cancer
[61][62]. Moreover, recent evidence suggested an association between the use of BPs and reduced risk of endometrial cancer, mainly in postmenopausal women
[63]. However, the known adverse effects of BPs
[64][65] justify developing safe and effective bisphosphonate conjugates for adjuvant treatment of metastatic bone cancers. Indeed, many BP-conjugates containing anticancer drugs were previously tested
[66], while other authors have proposed encapsulation in liposomal nanoparticles
[67] to improve uptake and efficiency, and to decrease toxicity.
Hybrid vanadium-bisphosphonates (V-BPs) (
Figure 1C) showed anticancer activity
[43]. BPs complexed with polyoxidovanadates with nuclearities ranging from 3 to 6, V
6(Ale)
4, V
5(Ale)
2, V
5(Zol)
2, and V
3(Zol)
3, inhibited the proliferation of different tumor cell lines, such as MCF-7 (breast cancer), NCI-H460 (lung cancer), and SF-268 (glioblastoma) (
Table 1)
[43]. While the calculated IC
50 values were comparable with those obtained when treating cells with decavanadate (Na
6[V
V10O
28]), they were much lower than for the ligands themselves, especially for free alendronate (Ale), which was also considerably less potent than zoledronate (Zol) (
Table 1). Nevertheless, the differences between the four V-BPs were minimal, suggesting that the BPs do not play a major role in inhibiting cell viability and that most of the activity comes from the inorganic part. Compared with other hybrid BPs, polyoxidometalates (POMs) such as with Mo
VI and W
VI, the complexes containing V
IV,V cores, showed the greatest inhibitory potential
[43].
Table 1. Human tumor cell growth inhibition upon vanadium complexes with approved drugs and for decavanadate. IC
50 (µM) determined by MTT ((3-(4,5-dimethylthiazole-2-yl)-2,5-diphenylte-trazolium bromide) cell proliferation assay. The values were collected from
[43].
Interestingly, both V
5(Ale)
2 and V
3(Zol)
3 complexes also showed antiparasitic potential, reducing the viability of
Leishmania tarentolae cultures, while the ligands alone (i.e., alendronate (Ale) or zoledronate (Zol)) did not show activity against these parasites
[68], highlighting the therapeutic potential of such vanadium-based compounds.
4.3. Metformin-Decavanadate
Metformin belongs to the biguanide group of antidiabetic drugs that have been widely used for many years
[69][70]. Based on its safety profile and the current knowledge of its mechanisms of action, metformin has additional approved medical off-label indications (namely obesity and polycystic ovary syndrome) and has accumulated evidence to be repositioned for the treatment of age-related diseases (such as sarcopenia), inflammatory diseases, and cancer
[71][72][73]. Almost two decades ago, the first epidemiological evidence revealed that diabetic patients taking metformin were less prone to developing cancer
[74]. Metformin is, by far, the most frequently studied antidiabetic agent in clinical trials (typically combined with chemotherapy)
[75]. However, it is currently debatable whether metformin as a cancer therapeutic is truly effective
[73][76][77], despite new evidence regarding its potential benefits when combined with immunotherapy
[78][79].
After its synthesis and characterization
[80], metformin-decavanadate (Metf-V
10) (
Figure 1B) was proposed for the treatment of diabetes
mellitus, and found to have hypoglycemic properties and an excellent safety profile in animal models
[42][81][82]. Recently, it was further tested for its potential anticancer action in hepatoma and melanoma cell lines
[83][84]. When compared to the decavanadate sodium salt (V
10), a higher concentration was needed to induce 50% inhibition of Ca
2+-ATPase enzyme activity (IC
50) (around six-fold), although similar IC
50 values were obtained in UACC-62 melanoma cells viability (1.3-fold higher in V
10 (
Figure 1A) compared to Metf-V
10)
[84]. In the hepatoma HepG2 cells, by contrast, a 3-fold higher IC
50 was observed for Metf-V
10 compared to V
10 [83]. Despite these inconsistencies, both studies showed PI3K/AKT signaling pathways were activated by both Metf-V
10 and V
10 in a dose-dependent manner
[83][84], suggesting that AKT hyperactivation could be one of the mechanisms of action involved, independent of the cancer cellular context.
4.4. Cetirizine-Based Oxidovanadium (IV) Complex
Cetirizine (CTZ) is an antihistamine medicine commonly used for treating allergic diseases. Other antihistaminic drugs showed antitumoral potential, particularly in colorectal cancer, associated with enhanced immune response
[85]. Improved cancer survival was associated with the administration of the antihistamine desloratadine, specifically in patients with tumors that respond to therapy with immune checkpoint inhibitors, while lower evidence was found for CTZ, which was only observed in gastric, pancreatic, and ovarian cancer
[86]. However, others showed that the concomitant use of CTZ and anti-PD-1 monoclonal antibodies led to increased progression-free survival in patients with stage IIIb-IV melanoma, suggesting that the effect of CTZ may synergize with immunotherapies enhancing its efficacy
[87].
Recently, the propensity for DNA binding and biological potency of different VO
2+ complexes was evaluated by absorption titration and electrophilicity, respectively. Their behavior on a specific protein in colon cancer cells was also studied using molecular docking
[44]. The cetirizine-based oxidovanadium(IV) complex ([VO(CTZ)
2].2H
2O) (
Figure 1D) showed enhanced binding affinity to the studied protein when compared with the free ligand (i.e., CTZ). Based on the quantitative structure–activity relationships (QSAR) model, a prediction of effective activity against colon cancer was obtained for the CTZ complex (PRED IC
50 = 1.45 μM) (
Figure 3). When performing cellular in vitro experiments of cytotoxicity (sulforhodamine B method), the IC
50 of [VO(CTZ)
2].2H
2O was comparable to the predicted value for the human colon cancer cell line HCT116 (2.11 μM) (
Figure 3), and over 300 times higher for the normal cell line LLC-MK2 (649.8 μM). Interestingly, when compared to cisplatin (2.13 μM), the [VO(CTZ)
2].2H
2O complex showed similar IC
50 values, other than presenting the highest K
b value (1.40 × 10
6 M
−1) upon DNA interaction, which implies that the compound has a better binding ability compared with other vanadium compounds and its ligands
[44].
Figure 3. Predicted and experimental anticancer activity of cetirizine (CTZ) and [VO(CTZ)
2] 2H
2O in colon cancer. The IC
50 values were extracted from
[44].
The authors of the above study also synthesized and characterized other drug-based oxidovanadium(IV) complexes, namely with carbimazole ([VO(SO
4)(CBZ)] 8H
2O), lornoxicam ([VO(LOR)
2] SO
4) and sulfonamide ([VO(SO
4)(SCZ)] 7H
2O), though those were considered with lower biological potency and less capacity as anticancer agents, compared to the cetirizine complex
[44].
4.5. Clotrimazole (CTNZ), Miconazole (MNZ), and Pantoprazole (PNZ) Vanadyl-Based Complexes
Imidazole derivates are used as anticancer agents, namely dacarbazine and temozolomide, or zoledronic acid (
referred to in Section 4.2), among many other drugs
[88][89]. Additional examples of medicines comprising this five-member ring molecule containing a nitrogen atom include clotrimazole (CTNZ), miconazole (MNZ), and pantoprazole (PNZ), which are traditional antifungal (CTNZ, MNZ) and proton pump inhibitor (PNZ) medications. Nevertheless, there is experimental evidence they may be repositioned to treat cancers, such as hepatocellular carcinoma
[90], bladder cancer
[91], breast cancer
[92], glioblastoma
[93], gastric cancer
[94], and others.
The aforementioned imidazole molecules were reacted with oxidovanadium(IV) salt and the following complexes were obtained: [VO(SO
4)(CTNZ)(H
2O)]H
2O (
Figure 1E), [VO(SO
4)(MNZ)
2] H
2O (
Figure 1F), [VO(PNZ)
2]SO
4.2H
2O (
Figure 1G)
[95]. After treating the hepatocellular carcinoma HepG2 and the breast adenocarcinoma MCF-7 human cell lines for 24 h, all oxidovanadium(IV)-based imidazole drug complexes showed either comparable (MCF-7 cells) or lower (HepG2 cells) IC
50 values compared to cisplatin (
Figure 4), evaluated by the MTT metabolic assay
[95]. When analyzing their binding affinities as targeted drug molecules with specific hepatocellular carcinoma and breast cancer proteins, the authors of the latter study obtained higher molecular docking scores for all three complexes compared to those for the free imidazole ligands
[95].
Figure 4. Experimental anticancer activity of the imidazole-based oxidovanadium(IV) complexes [VO(SO
4)(CTNZ)(H
2O)]H
2O, [VO(SO
4)(MNZ)
2] H
2O, [VO(PNZ)
2]SO
4.2H
2O in HepG2 and MCF-7 cell lines. The IC
50 values were obtained from
[95]. Abbreviations: CTNZ, clotrimazole; MNZ, miconazole; PNZ, pantoprazole.
Over the last 25 years, different approved drugs were used as ligands in different vanadium complexes (Figure 5), highlighting novel potential therapeutic candidates based on drug repurposing.
Figure 5. Timeline of selected complexes of marketed-approved drugs with transition metals, synthesized and characterized over the past 25 years. Chronological representation of each significant publication. For each complex represented, the last name of the first author and year of publication is shown
[43][44][51][53][80][83][84][95][96]. Abbreviations: Asp-VO, vanadyl(IV)–aspirin complex; Nap-VO, vanadyl(IV) complex with naproxen; V-BP, hybrid vanadium-bisphosphonates; Metf-V10, metformin-decavanadate; Mo-BP, polyoxidomolybdate-bisphosphonates; VO-CTZ, cetirizine-based oxidovanadium(IV) complex; VO-PNZ, oxidovanadium(IV)-based pantoprazole complex.