Repurposing Therapeutic Drugs Complexed to Vanadium in Cancer

Abstract

Repurposing drugs by uncovering new indications for approved drugs accelerates the process of establishing new treatments and reduces the high costs of drug discovery and development. Metal complexes with clinically approved drugs allow further opportunities in cancer therapy-many vanadium compounds have previously shown antitumor effects, which makes vanadium a suitable metal to complex with therapeutic drugs, potentially improving their efficacy in cancer treatment. In this review, covering the last 25 years of research in the field, we identified non-oncology-approved drugs suitable as ligands to obtain different vanadium complexes. Metformin-decavanadate, vanadium-bisphosphonates, vanadyl(IV) complexes with non-steroidal anti-inflammatory drugs, and cetirizine and imidazole-based oxidovanadium(IV) complexes, each has a parent drug known to have different medicinal properties and therapeutic indications, and all showed potential as novel anticancer treatments. Nevertheless, the precise mechanisms of action for these vanadium compounds against cancer are still not fully understood.

Keywords: cancer treatment; decavanadate; drug repurposing; vanadate; vanadium complexes.

Figure 1

Structures of vanadium compounds and complexes with approved drugs. (A) Structure of the decameric species of vanadate, decavanadate, V₁₀O₂₈^6-. 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 (H₂Metf)₃[V₁₀O₂₈]·8H₂O. Water molecules are omitted for clarity [42]; (C) Polyhedral representation common to the Mo₆L₂ (where L corresponds to a ligand, either alendronate (Ale) or zoledronate (Zol)) POM frameworks, green tetrahedral = PO₃C, orange polyhedra = MoO₆ [43]; (D) Oxidovanadium(IV) complexes with cetirizine, [VO(CTZ)₂] 2H₂O [44]; (E) Clotrimazole oxidovanadium(IV) complex [VO(SO₄)(CTNZ)(H₂O)]H₂O; (F) Miconazole oxidovanadium(IV) complex, [VO(SO₄)(MNZ)₂] H₂O; (G) Pantoprazole oxidovanadium(IV) complex, [VO(PNZ)₂]SO₄.2H₂O; (H) Oxidovanadium(IV) complexes with Schift based compounds, such as for ibuprofen and naproxen [45]; (I) Oxidovanadium(IV) chrysin complex [46].

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).

Figure 3

Predicted and experimental anticancer activity of cetirizine (CTZ) and [VO(CTZ)₂] 2H₂O in colon cancer. The IC₅₀ values were extracted from [44].

Figure 4

Experimental anticancer activity of the imidazole-based oxidovanadium(IV) complexes [VO(SO₄)(CTNZ)(H₂O)]H₂O, [VO(SO₄)(MNZ)₂] H₂O, [VO(PNZ)₂]SO₄.2H₂O in HepG2 and MCF-7 cell lines. The IC₅₀ values were obtained from [95]. Abbreviations: CTNZ, clotrimazole; MNZ, miconazole; PNZ, pantoprazole.

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 [43,44,51,53,80,83,84,95,110]. 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.