Polyoxometalates as Potential Next-Generation Metallodrugs in the Combat Against Cancer

Abstract

Polyoxometalates (POMs) are an emerging class of inorganic metal oxides, which over the last decades demonstrated promising biological activities by the virtue of their great diversity in structures and properties. They possess high potential for the inhibition of various tumor types; however, their unspecific interactions with biomolecules and toxicity impede their clinical usage. The current focus of the field of biologically active POMs lies on organically functionalized and POM-based nanocomposite structures as these hybrids show enhanced anticancer activity and significantly reduced toxicity towards normal cells in comparison to unmodified POMs. Although the antitumor activity of POMs is well documented, their mechanisms of action are still not well understood. In this Review, an overview is given of the cytotoxic effects of POMs with a special focus on POM-based hybrid and nanocomposite structures. Furthermore, we aim to provide proposed mode of actions and to identify molecular targets. POMs are expected to develop into the next generation of anticancer drugs that selectively target cancer cells while sparing healthy cells.

Keywords: antitumor agents; biological activity; cancer; nanoparticles; polyoxometalates.

Figure 1

Overview of common POM archetypes. a) Keggin, b) Wells–Dawson, c) Anderson, d) Lindqvist, e) decavanadate, f) sandwich Keggin, g) double Keggin, h) heptamolybdate, i) α‐ and j) γ‐octamolybdate, k) Preyssler, l) Strandberg, and m) Krebs‐type structure. Blue polyhedra are {MO₆} (M=any addenda atom), light green polyhedra {XO_n} (X=heteroatom), light green spheres sodium, light blue polyhedra {WO₆}, light cyan polyhedra {MoO₆}, gray polyhedra {VO₆}, purple polyhedra and spheres {YO_n} and Y (Y=second heteroatom), orange polyhedra {PO₄}, red spheres oxygen.

Figure 2

General structure of the POM‐BP compounds M₆L₂ and M₄L₂X. L=bisphosphonate side chains, which are depicted at the bottom. The phosphonate group is depicted in ball and stick mode (orange spheres, phosphorous; red spheres, oxygen). Blue polyhedra are {MO₆} (M=V, Mo, W), purple polyhedra {XO₆} (X=Fe^III, Mn^II/III), green sticks carbon, red spheres oxygen.

Figure 3

Structures of POM–quinolone hybrids. a) [Cu₂(Enro)₃H₂O][SiW₁₂O₄₀] (left) and H₂[Ni(Enro)₂][SiW₁₂O₄₀] (right). The adjacent POM found in the crystal structure of H₂[Ni(Enro)₂][SiW₁₂O₄₀] is indicated by a transparent molecule; however, in solution this site is most probably occupied by a solvent molecule. b) [HPPA]₅[PW₁₁CdO₃₉] (left) and [Cu(PPA)₂]₂[PW₁₂O₄₀] (right). Red arrows indicate the accessible interaction sites. Light blue polyhedra are {WO₆}, orange polyhedra {PO₄}, green sticks carbon, dark blue sticks nitrogen, dark green sticks fluorine, brown spheres copper, green sphere nickel, yellow sphere cadmium, red sticks and spheres oxygen.

Figure 4

Biomolecule‐functionalized Anderson structures. Cyan polyhedra are {MoO₆}, magenta polyhedra {MnO₆}, green sticks carbon, dark blue sticks nitrogen, red spheres oxygen.

Figure 5

General structure of the aromatic organoimido (a), benzoyldiazenido (b), and aliphatic organoimido‐substituted hexamolybdates (c). Cyan polyhedra {MoO₆}, green sticks carbon, dark blue sticks nitrogen, red sticks and spheres oxygen.

Figure 6

Structure of POM‐AMB‐acy. For clarity, the structural formula of AMB (green) and acy (red) is additionally depicted. Cyan polyhedra {MoO₆}, green sticks carbon, dark blue sticks nitrogen, red sticks and spheres oxygen.

Figure 7

The pH‐responsive POM‐based hydrogels. Dashed lines represent POM–polymer interactions.

Figure 8

Illustration of the spontaneous assembly of the POM–lipid hybrid into a vesicle. Light blue polyhedra are {WO₆}, orange polyhedra {PO₄}, purple sphere silica, red spheres oxygen.

Figure 9

Representation of the POM‐MSN‐dye‐DOX system. At the top of the figure the disulfide bond (orange) is intact and the attached POM‐dye (dye=green) hybrid blocks the release of DOX molecules (big red spheres) from the MSN pores. After disulfide cleavage by GSH, the POM‐dye hybrid and DOX are released. Light blue polyhedra {WO₆}, gray polyhedra {VO₆}, tan polyhedra {GeO₄}, small red spheres oxygen.

Figure 10

Representation of the destructive interaction between POMs and membranes. The POM adsorbs to the membrane surface and forms a stable POM–lipid conjugate that desorbs from the membrane.

Figure 11

Illustration of most of the proposed modes of action of antitumoral POMs. a) POM induced inhibition of ATP synthesis by interfering with the electron transfer chain (represented as dark blue entities, the inset shows a zoomed view of the chain). b) POM induced increase in ROS‐level (for example by oxidizing cell components) and depletion of the GSH pool (by GSH oxidation). c) POM induced enhancement of the expression of pro‐apoptotic components (Bax and Bim) and the reduction of the expression of anti‐apoptotic components (bcl‐2 and NF‐κB). d),e) Activation of the p53 and/or p38 pathway by POMs. Please note: the circles reading p38 and p53 do not represent the respective protein but the pathways. f) Induction of apoptosis by direct DNA damage. g),h) POM‐mediated inhibition of angiogenesis via interaction with bFGF and VEGF leading to the disruption of the VEGF/bFGF‐receptor interactions (receptors are indicated as yellow and brownish channels). Without VEGF/bFGF‐receptor binding, the ERK pathway cannot be activated leading to the breakdown of angiogenesis. i) Inhibition of ectonucleotidases by POMs leads to a distortion in the concentrations of nucleotides (NTP, NDP, and NMP) and nucleosides (Ns), which negatively affects the functioning of cancer cells. j) Inhibition of HDAC by POMs leads to the accumulation of acetylated histones, causing fatal changes in the expression of genes. k) Inhibition of P‐type ATPases has fatal effects on the cellular ion homeostasis. l) Decavanadate‐induced mitochondria membrane depolarization. m) Inhibition of other proteins that affect cell viability (for more details, see text of Section 2.3.1 and 3.2.5, and references therein). n) POM hybrids loaded with siRNA (siRNA is depicted as red RNA structure) downregulate HIF‐1, leading to the impairment of angiogenesis and the adaptation of cancer cells to the hypoxic environment. o) Immunostimulating activity of POMs by promoting the expression of antibodies and immune‐related components (for example, NK cells). The figure depicts the activation of NK cells via antibody binding enhancing the recognition of tumor cells (antigens are depicted as purple triangles) by NK cells. Dotted lines indicate that the reason of activation/deactivation (for example, enhanced/decreased expression) of certain components is not known. The release of cytochrome c (purple circle) triggers the apoptotic machinery of the cell, which ultimately activate the final executers of apoptosis (caspases).

Figure 12

Putative POM‐binding site of bFGF. a) Crystal structure of human bFGF (PDB entry 1BFF137) with the putative binding site being marked by a red circle. Side chains of amino acids that potentially contribute to heparin binding are shown as sticks. b) Coulombic surface representation of bFGF is illustrated with blue surfaces representing regions exhibiting a positive potential, whereas gray and red surfaces possess neutral and negative potentials, respectively. c) Zoom view and dimensions of the putative POM‐binding site. d) Polyhedra structures and dimensions of the Keggin and Wells–Dawson anions for easier comparison. Blue polyhedra are {MO₆}, green polyhedra {XO₄}, green sticks carbon, dark blue sticks nitrogen, red sticks and spheres oxygen.

Figure 13

POM‐binding sites of NTPDase1 from Legionella pneumophila. The structure of bacterial NTPDase1 consists of two domains (cyan and green cartoon) with the interface forming the active site cleft. The depicted structure is taken from PDB entry 4BVO142 as model example. The interacting amino acid residues are shown as sticks. Light blue spheres are tungsten, cyan spheres molybdenum, gray spheres vanadium, cyan/green sticks carbon, dark blue sticks nitrogen, red sticks oxygen. Dashed lines represent POM–protein interactions. Note that octamolybdate forms a covalent bond with a serine (Ser 127).