Vanadium, a Promising Element for Cancer Treatment

Abstract

In this century, cancer is one of the most important causes of death worldwide, and the need for the development of new treatment options is imperative. The use of metal-based compounds in cancer treatment has increased significantly due to certain properties of these elements, and vanadium has been one of the most studied transition metals in recent decades. Vanadium compounds are being explored as an option for cancer treatment because of their wide range of action mechanisms such as the induction of oxidative stress, DNA damage, cell cycle arrest, induction of apoptosis and regulation of the autophagy process, among the most important mechanisms. Their compounds have been demonstrated to be effective against the cancer types with the highest incidence and mortality rates worldwide, such as lung and breast cancer, with promising results. This review discusses a variety of new vanadium compounds, indicating their mechanisms of action and the neoplasms in which they have shown effectiveness.

1. Introduction

Various factors act as risk factors for developing cancer. In this century, cancer is the cause of one out of every four non-communicable disease-related deaths worldwide (22.8%). When age is considered a risk factor for premature death, cancer occurs in three out of 10 subjects aged 30 to 69 years in 177 of 183 countries. Cancer mortality among women is disproportionately high, primarily due to breast or cervical cancer. Overall, lung cancer is the leading cause of morbidity and mortality, according to the most recent report from 2022 [1]. This problem has other consequences, such as the need for specialized health professionals and more oncology centers with the necessary equipment and medications to properly treat patients. However, this places a significant economic burden on health systems worldwide [2].

One option for cancer treatment is chemotherapy, which is expensive; furthermore, the heterogeneity that can be found in cancer requires the use of more toxic drugs and those to which resistance can develop [3]. For these reasons, the search for less expensive effective antitumor drugs with high selectivity, good bioavailability and low toxicity options is ongoing. Metal compounds are a source of anticancer molecules, such as platinum compounds, which have demonstrated effectiveness in various cancer treatments. Cisplatin was the first metallic compound used against cancer and throughout history, since 1978 when it was approved by the FDA to be used as a chemotherapy agent against ovarian and testicular cancer, it has been used against numerous types of cancer such as bladder, lung, cervical, gastric cancer, melanoma, among others [4].

The rise in the use of platinum (Pt) as an anticancer agent has spurred the search for other metal-based compounds with similar effects but lower toxicity and fewer side effects. Cisplatin has been widely used, but it is important to mention that it produces numerous undesirable adverse effects, such as nephrotoxicity, neurotoxicity, ototoxicity, vomiting, anemia, myelosuppression, and cytotoxicity in normal cells [5,6]. Furthermore, cancer cells acquire resistance relatively quickly [4,5]. Platinum compounds are capable of increasing ROS production and binding to genomic or mitochondrial DNA, causing damage that blocks replication, transcription, and translation, as well as activating signaling pathways that lead to apoptosis or necrosis [4]. The toxicity of cisplatin led to the development of subsequent generations of drugs based on the same metal, aimed at reducing adverse effects; however, these have not shown substantial advantages compared to cisplatin.

Some of the most widely used have been copper (Cu), gold (Au), iridium (Ir), iron (Fe), rhenium (Re), ruthenium (Ru), osmium (Os), Zinc (Zn), vanadium (V), among others [5,7,8,9,10]. The use of metal-based compounds in cancer treatment has increased significantly due to certain properties of these elements: multiple oxidation states and coordination numbers, accessible redox states and kinetic and thermodynamic characteristics that allow them to exert antiproliferative, proapoptotic and antiangiogenic effects, acting as modulators of key signaling pathways [8,9,10,11].

Table 1. Advantages and limitations in the use of metal based anticancer complexes compared to platinum drugs.

Metal Compounds	Biologic Effects	Advantages	Limitations
Copper (Cu) complexes	Cytotoxic activity, mitochondrial dysfunction, ROS production, apoptosis activation and cell migration inhibition [5,9].	More easily absorbed by tumor cells than by normal cells, tolerable toxicity and good selectivity towards tumor cells instead of non-tumor cells [5,9].	Angiogenesis and metastasis are greatly aided by copper [9].
Gold (Au) complexes	DNA damage, mitochondrial disfunction, autophagy, potential antimetastatic effect, tubulin polymerization inhibition, ROS production, cell cycle arrest, apoptosis, topoisomerase inhibition and specific kinase inhibition [9,12,13].	Gold is a biocompatible and inert metal. In vitro and in vivo antitumor properties towards several human cancer cells [12,14].	Instability of ligands in Au complexes, low solubility, toxicity against normal cells, drug resistance [9,12].
Iridium (Ir) complexes	Cytotoxicity, ROS production, mitochondrial dysfunction and apoptosis [5,9].	Water tolerance, fewer adverse effects, complexes can form wide range of versatile structures, higher kinetic degree of ligand substitution, efficacy against cisplatin resistant cells [5,9,15].	The mechanisms by which Ir compounds exert their effects are not yet fully elucidated, as studies on their antitumor activity are still in the preliminary stages [9].
Iron (Fe) complexes	ROS production, cytotoxicity, DNA damage, disturbance of iron homeostasis, [5,16].	As an essential element, this metal has specific physiological processes for uptake and excretion. Variety in structures of its complexes, elevated anticancer activities against a broad range of cancer cell lines, negligible effects on noncancerous cells [16].	Interactions with endogenous iron and disruptions of iron homeostasis occur in the case of labile complexes [16].
Rhenium (Re) complexes	DNA damage, cytotoxic activity, ROS production and apoptosis [17].	Various oxidation states enables the formation of diverse ligand types and coordination structures [17].	The use of Re in cancer therapy is still in its early stages, and the mechanisms of action of these compounds are not yet fully understood. A limited number of studies have examined the in vivo applicability of Re compounds [17].
Ruthenium (Ru) complexes	Tumor cell cycle arrest, apoptosis, ROS production, protein kinases inhibition, angiogenesis inhibition [9,12,18].	Slow ligand exchange kinetics, lower toxicity, selective cytotoxic activity in vitro against cancer cells. Several examples of Ru complexes exhibiting in vivo anticancer activity; real clinical potential. Efficacy against drug-resistant malignancies [9,18].	Not all mechanisms of action have been elucidated. The effect on metastasis has been poorly studied [9,18].
Osmium (Os) complexes	Protein inhibition (such es Hypoxia inducible factor—HIF), DNA interactions, antiproliferative activities, ROS production and cell death [5,9,19].	Osmium’s higher oxidation states are stable, antineoplastic potential both in vitro and in vivo, no cross-resistance with cisplatin in cancer cells [9,19].	The mechanisms of action of Os compounds are poorly understood, as their antitumor effectiveness has been studied less extensively than that of other metallic complexes [19].
Zinc (Zn) complexes	ROS production, DNA fragmentation and cytotoxicity [20,21].	As an essential metal, there are biological mechanisms for its absorption and elimination, and it is less toxic at higher doses compared to other metals such as Fe and Cu [12,20,21].	Interactions with endogenous zinc and disruptions of zinc homeostasis occur in the case of labile complexes [20,21].

includes some of the metals that have been used to develop anticancer drugs. These metals show various advantages compared to Pt compounds; however, there are also some limitations in their use, which are mentioned below.

In the field of cancer research, various V compounds have been synthesized to achieve better tolerance, higher selectivity and reduced toxicity in cancer treatment.

Vanadium compounds are being explored as an option because of their wide range of action mechanisms, such as disrupting cancer cell metabolism, producing reactive oxygen species (ROS), interfering with the epithelial–mesenchymal transition signaling pathway, and inhibiting focal adhesion kinase (FAK) or Notch-1 signaling pathways [22,23,24,25,26]. To reduce the toxicity of V compounds and increase their lipophilicity and transport across cell membranes, a variety of ligands have been incorporated, including bisphosphonates, non-steroidal anti-inflammatory drugs, metformin, cetirizine, and imidazole derivatives, with promising results [24,26,27].

This review discusses a variety of vanadium compounds, indicating their mechanisms of action and the neoplasms in which they have shown effectiveness. Our focus remains exclusively on research conducted from 2015 onwards.

2. Vanadium and Its Antineoplastic Potential

Vanadium is a transition metal from the 3d series of the periodic table, which means it exhibits several oxidation states: the most common being +2, +3, +4, and +5 [28,29,30]. It is used in alloys to enhance strength when combined with other metals [30,31] and is commonly found in soil, bedrock, groundwater, fossil fuels like petroleum, and in living organisms [32,33]. It has been described as an essential micronutrient in some living organisms, such as fungi and worms. However, in humans, it is found in concentrations of up to 100 μg without any reported deficiency symptoms; therefore, it is not considered a micronutrient [29,31,32].

This metal has shown antidiabetic, anticancer, antiparasitic, and antituberculosis properties. Its therapeutic properties are due to the metal’s chemistry; its species and complexes are easily interconverted [29,34]. In the last decade, it has gained relevance in anticancer applications due to its ability to inhibit and induce various pathways and enzymatic pathways and complexes associated with different types of cancer [26,28,32,34,35]. The first vanadium compounds tested as anticancer agents include salts such as: ammonium metavanadate (NH₄VO₃), sodium metavanadate (NaVO₃), and potassium metavanadate (KVO₃), and vanadyl sulfate (VO₄SO₄). Additionally, four commercially available forms of vanadium have been used in studies: sodium decavanadate (Na₆V₁₀O₂₈), vanadium pentoxide (V₂O₅), vanadyl dichloride (VOCl₂), and vanadium(III) chloride (VCl₃). In recent decades, hundreds of compounds of this metal have been developed, including nanoparticles and a wide range of organic and inorganic complexes, which are intended to induce desirable biological effects for therapeutic use. The most promising compounds have been tested in both in vitro and in vivo biological models to demonstrate low toxicity and higher efficacy [26,35,36].

The therapeutic effects of vanadium depend on several factors, such as oxidation state, dose, and route of administration. Its mechanism can be cytotoxic, but in this case, which is advantageous when targeting tumor cells [26]. Kostenkova and colleagues [35] and Singh and colleagues [26], reviewed the following anticancer properties:

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Inhibition of enzymes, such as tyrosine phosphatase, promoting the activation of tyrosine kinases and oncogene suppressors, which induces apoptosis in cancer cells.

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DNA interaction with vanadium complexes inserting between DNA strands, causing cell cycle breaks or alterations. Some other compounds, such as ‘Metvan’, which has an extensive aromatic system strongly coordinated with V, can also interact with DNA through aromatic π-stacking, which interferes with DNA replication and uncontrolled cell division.

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Generation of reactive oxygen species (ROS) increasing the production of superoxide and hydrogen peroxide, leading to a state of oxidative stress and apoptosis of cancer cells.

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Differentiation between normal and cancer cells, with some vanadium complexes such as VO(maltol)₂, which showed selectivity in affecting cancer cells while sparing normal cells.

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Inhibition of specific demethylases, through the vanadium complex bearing tridentate shiff base ligands, which showed potential to inhibit lysine-specific demethylase (LSD1), an important target in cancer treatment.

The first study describing the antineoplastic activity of a vanadium compound, vanadocene dichloride (C₅H₅)₂VCl₂, dates back to 1965 [37]. Since then, research on vanadium and its relationship with cancer has experienced significant growth. Among the cancer types in which vanadium’s anticancer activity has been observed are breast, liver, colon, and hematopoietic tissue cancer, among others [36,38]. In recent years, its effect on other types of cancer, such as skin, bone, and lung cancer, to name a few, has also been explored. In recent decades, the use of V complexes, such as those with flavonoids, has achieved significant progress in cancer research due to their potential for action on various cancer cell lines, in addition to the in vivo effects that have been described. This review presents the results of in vivo and in vitro studies, with special emphasis on those conducted in the last decade. Please note that we have selected a number of publications, and as such, our review does not aim to address all studies that have been documented.

3. In Vivo and in Vitro Evidence of Vanadium’s Anticancer Activity

As previously mentioned, the anticancer activity of vanadium has been widely explored in recent decades, and its compounds have emerged as alternative antitumor agents to platinum. In a comprehensive review conducted by Bishayee and colleagues in 2010, the findings up to that point regarding the use of vanadium compounds in in vivo preclinical models were summarized. Among the most common cancer types are breast, colorectal, liver, and hematologic cancers [38]. Cancer treatment is a complex process that faces significant challenges. Conventional clinical treatments include surgery, radiotherapy, and chemotherapy. Currently, oncology is seeking to develop new, safer, and more effective drugs, and vanadium compounds have been proposed as promising therapeutic strategies.

New evidence from the last decade regarding the antineoplastic effects of vanadium in both in vitro studies and in vivo models, along with the mechanisms associated with them, is described below.

3.1. Breast Cancer

According to current data from the Global Cancer Observatory (GLOBOCAN), breast cancer is the leading cause of death from malignant neoplasms in women [39] and ranks second in cancer mortality, just after lung cancer. In vivo evidence has shown that in 1-methyl-1-nitrosourea (MNU)-induced breast cancer models, VOSO₄ reduces the incidence and number of mammary tumors in rats. Likewise, in 7,12-dimethylbenz(a) anthrancene (DMBA)-induced mammary cancer models, NH₄VO₃ suppresses hyperplasia and reduces the incidence, multiplicity, and size of breast tumors. In addition, vanadocene dichloride (C₅H₅)₂VCl₂ has proven effective in the treatment of preexisting breast tumors [38].

Over the last decade, additional evidence has emerged confirming the anticancer effect of vanadium in vivo. A study by Roy and colleagues demonstrated the antineoplastic activity of a vanadium compound coupled with quercetin (flavonoid) in a DMBA-induced mammary carcinogenesis model in female Sprague–Dawley rats. The animals treated with the complex exhibited the same histological characteristics as controls without developing hyperplasia or neoplastic lesions. Furthermore, the treatment increased cell death by apoptosis and reduced cellular proliferation. In the same study, the authors observed pro-apoptotic effects in MCF-7 human breast cancer cells treated with the compound, including an increase in p53, caspases 3 and 9, DNA fragmentation, and a decrease in Akt, mTOR, and VEGF [40].

In another study, Tian and colleagues investigated the effects of NH₄VO₃ in a subcutaneous xenograft model using 4T1 murine breast cancer cells in female BALB/c mice. Their findings demonstrated a reduction in tumor volume, lower development of microvasculature, and an increase in apoptosis. In vitro, the treatment of 4T1 cells showed inhibition of cell proliferation, increased reactive oxygen species (ROS), arrest of the cell cycle in G2/M phase, decreased mitochondrial membrane potential, and induction of apoptosis [41]. Other compounds tested against breast cancer include oxidovanadium complexes with other molecules. In vitro, Kalındemirtaş and colleagues analyzed the effect of two vanadium oxide compounds (VO1a and VO1b) on the MDA-MB-231 and MCF-7 cell lines. The authors reported a decrease in the activity of the multidrug resistance transporter ABCG2 and an increase in apoptosis, but not in necrosis [42]. In another study, an IV- oxidovanadium imidazole complex (VOL) was used in MCF-7 cells; VOL administration induced apoptosis, ROS production, an imbalance in the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), lipid peroxidation, and a reduction in mitochondrial membrane potential [43].

The same research group evaluated the in vivo and in vitro effects of the 1-methylimidazole oxidovanadium complex (OVMI). In vivo, in breast tumors derived from 4T1 cells in female BALB/c mice, the compound reduced tumor volume by decreasing proliferation (as shown by lower Ki67 expression), triggered apoptosis, and exhibited anti-metastatic effects by reducing metastasis markers (E-cadherin and N-cadherin) in tumor tissues. In vitro, treatment of MDA-MB-231 cells with the complex led to delayed proliferation, apoptosis, mitochondrial membrane potential alteration, and increased ROS production. The authors also reported that OVMI was biocompatible and non-toxic in normal cells in vivo [44].

In contrast, a study evaluating nitrilotriacetate-based N-heterocyclic vanadium (IV) salts in MCF-7 cells found that the compound induced DNA fragmentation and arrested the cell cycle in G0/G1 phase. However, because the compound also affected normal cells, the authors ruled out its therapeutic potential for in vivo use [45].

Finally, in recent years, vanadium nanoparticles have been tested against different types of cancer, including breast cancer. In MDA-MB-231 cells treated with nanoparticles of this metal (VnNp), increased ROS production and decreased SOD levels, cell cycle arrest in the G2/M phase, and apoptosis were reported. Furthermore, ultrastructural observation showed the presence of autophagosomes and VnNp in the cytoplasm and mitochondria of these cells [46].

3.2. Liver Cancer

Liver cancer is characterized globally by its high prevalence and mortality. According to GLOBOCAN data, it ranks sixth in both incidence and mortality, as it is one of the most common types of digestive malignancy worldwide [39]. Most deaths from this disease are attributed to hepatocellular carcinoma (HCC), which ranks third among causes of death from digestive system cancer [47].

The review by Bishayee and colleagues includes in vivo evidence demonstrating the anticancer activity of vanadium in models of hepatocellular carcinoma induction with diethylnitrosamine (DENA). In these models, the administration of NH₄VO₃ in drinking water was able to inhibit the growth of preneoplastic lesions, significantly reduced the incidence, number, size, and multiplicity of hepatic neoplastic nodules; in other studies, it even prevented the formation of nodules and hepatocarcinoma. Moreover, the chemopreventive activity of vanadium has also been demonstrated in models of liver carcinogenesis induction with 2-acetylaminofluorene (2-AAF) [38].

Another compound tested both in vitro and in vivo against hepatocarcinoma is sodium orthovanadate (SOV). Suppression of proliferation, cell cycle arrest, apoptosis, and inhibition of autophagy were demonstrated in the human hepatocellular carcinoma cell lines HepG2, SK-Hep-1, and Hep3B. Using the same compound in vivo in an orthotopic xenograft model with BALB/C nude mice injected with HepG2 cells, the authors reported decreased tumor size, decreased proliferation index and microcirculatory density, and increased apoptosis due to mitochondrial damage [48].

The effect of oxidovanadium compounds on liver cancer cell lines has been demonstrated in vitro. In HepG2 cells independently exposed to NaVO₃, bis(maltolate)- oxidovanadium(IV) (VO(ma)₂) and bis(acetylacetonate)- oxidovanadium(IV) (VO(acac)₂) demonstrated inhibition of cell progression in the G1/S phase by regulating the ERK signaling pathway. Furthermore, it was found that these compounds exhibit greater selectivity toward cancer cells compared to normal hepatocytes of the L02 cell line [49]. On the other hand, Aliabad and colleagues confirmed that the vanadium complex 4-bromo-2-(((5-chloro-2-hydroxyphenyl) imino) methyl) phenol ([IV(L)] complex) induced early apoptosis and late necrosis/apoptosis in both HepG2 cells and L929 normal fibroblast cells, with a higher death rate in cancer cells and a lesser effect on normal cells [50].

The efficacy of vanadium nanoparticles has recently been tested in in vitro studies with liver cancer cells. Yang and colleagues demonstrated that vanadium-doped iron oxide (VIO) nanoparticles induce the death of murine hepatoma Hepa1-6 cells, in addition to having potential antiangiogenic activity since it was shown that human endothelial (HUVEC) and murine endothelial (C166) cell lines are also targeted by these nanoparticles [51]. In another study, the efficacy of cellulose-coated V₂O₅ nanoparticles on human hepatocellular carcinoma cell line (HuH-7.0) was verified by inducing morphological changes and cell death [52].

3.3. Colorectal Cancer

Currently, according to global data from GLOBOCAN, colorectal cancer is the third most diagnosed type and the second leading cause of cancer-related death worldwide [39]. Several studies have shown that vanadium compounds are used as antineoplastic agents in colon cancer, both in vitro and in vivo models.

In preclinical in vivo studies of 1,2-dimethylhydrazine (DMH)-induced colorectal cancer in rodents (rats and mice), NH₄VO₃ has demonstrated its anticancer activity by reducing the number and size of aberrant crypt foci, which are considered one of the first observable preneoplastic alterations in the development of colonic mucosal neoplasms. It also reduced the formation of adenomas and carcinomas [38].

Regarding in vitro studies, Sinha and colleagues reported the effect of the vanadium complex vanadyl N-(2-hydroxyacetophenone) glycinate [VO(NG)₂] on several cancer cell lines, including the human colorectal carcinoma cell line HCT-116. This compound induced cell cycle arrest in G2/M and apoptosis, without affecting peripheral blood mononuclear cells used as a normal control. The authors also reported glutathione (GSH) depletion and a subsequent increase in ROS levels [53]. Another compound tested is Metvan (4,7-dimethyl-1,10-phenathroline 7 sulphate oxidovanadium(IV)). León and colleagues demonstrated that this compound inhibits mitochondrial metabolism and reduces cell viability in the HT-29 human colon adenocarcinoma cell line [54].

In the last decade, oxidovanadium complexes coupled to flavonoids have also been tested in vitro on colon cancer cell lines. León and colleagues reported the action of the complex Na₂[VO(silibinin)₂]·6H₂O (VOsil) coupled with silibinin, and the complex [VO(chrysin)₂EtOH]₂ (VOcrys) coupled with chrysin, in HT-29 cells. Both compounds inhibited cell viability. It was identified that, upon exposure to these complexes, the proportion of oxidized and reduced glutathione was altered, which may be related to the effects found. Additionally, exposure to VOcrys induced cell cycle arrest at G2/M, while VOsil activated caspase-3, leading to apoptosis of the cells [55]. In another study, the luteolin complex [VO(lut)(H₂O)₂]Na₃·H₂O (VOlut) exhibited cytotoxicity against the CT26 colon carcinoma cell line, and at low concentrations the effect on the viability of normal colon epithelial cells was minimal. In the same study, an in vivo model with BALB/c mice was used to evaluate the effect of the VOlut complex on the metastatic capacity of CT26 cells (injected into the mice’s spleen capsule), from the spleen to the liver. VOlut behaved as a powerful antimetastatic agent, which was confirmed by observing the liver of mice treated with the complex in which no metastatic nodules appeared [56]. The mechanisms of action activated by vanadium were not explored in this study.

Roy and Chakraborty, on the other hand, demonstrated that the V-luteolin complex reduces cell proliferation in the HT-29 cell line and induces apoptosis. In an in vivo model using male Wistar rats, treatment with the compound at the highest dose exhibited the greatest chemotherapeutic potential by significantly reducing the formation of aberrant crypt foci and inducing apoptosis, in addition to increasing the antioxidant function of SOD, CAT, and glutathione (GSH) enzymes. The reported apoptotic effects are attributed to the activation of key proteins such as p53, Bax, and caspase-3, and the downregulation of Bcl2 and mTOR/Akt [57].

Regarding the use of nanoparticles, Xu reported reduced cell viability in several human colorectal cancer cell lines—Caco-2, COLO 320, DLD-1, HCT-15, HCT-116, and HT-29—when treated with vanadium-coupled Salvia officinalis nanoparticles (VNPs@Salvia officinalis). The author suggested that the observed effects might be due to the antioxidant activity of the nanoparticles, although this requires further investigation [58]. Additionally, zinc-chromium-vanadate nanoparticles (VCrZnO₄ NPs) exhibited anticancer effects through cytotoxicity against HCT-116 cells [59].

Finally, in another interesting study, Cheng and colleagues used VCl₃ to test its effect on glucose metabolism in murine colorectal cancer cells CT26 and MC38, given that tumor cells are known to develop various metabolic strategies that support malignancy progression. The results indicated that VCl₃ inhibited the activity of several enzymes (glucose-6-phosphate dehydrogenase [G6PD], lactate dehydrogenase [LDH], hexokinase [HK], and pyruvate kinase [PK]), thereby blocking glucose metabolism and leading to inhibited proliferation. The same study analyzed the effect of a nanosystem composed of glutaminase inhibitors (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide, BPTES) and vanadium, resulting in dual suppression of energy metabolism in both cell lines. This nanoplatform inhibited glucose metabolism and ATP synthesis, leading to suppressed proliferation, reduced viability, and apoptosis. The experiment was also replicated in vivo in BALB/c mice with tumors derived from CT26 and M38 cells, where results were consistent with the in vitro findings. Additionally, the study demonstrated that the nanoparticles enhance the vulnerability of colorectal cancer cells to chemotherapy and immunotherapy [60].

3.4. Hematological Neoplasms

Hematologic neoplasms involve the abnormal development of blood cells and their persistence in bone marrow, lymphomas, and lymph nodes. These diseases include leukemia, lymphomas, and myeloma [61]. Despite the development of targeted chemotherapy agents for some types of these neoplasms, others are still treated with highly toxic chemotherapeutic agents. Moreover, drug resistance remains a challenge, which is why potential treatments, some of them metal-based, continue to be studied.

In the field of hematological cancers, arsenic trioxide was approved in 2000 for patients with acute promyelocytic leukemia refractory to other treatments. Darinarsine, a glutathione derivative containing arsenic, is used in the treatment of refractory lymphomas, and cisplatin has been used in treatment-resistant leukemia [62]. The effect of vanadium compounds on hematological neoplasms has been studied in recent years, mainly through in vitro models, with promising results, some of which are presented below.

In vivo evidence has shown that in preclinical xenograft models using murine leukemia and Dalton’s lymphoma cells, (C₅H₅)₂VCl₂, NH₄VO₃, and other vanadium complexes increased survival in tumor-bearing animals [38], although the mechanisms by which they exert their action have only been explored in vitro.

In vitro studies in the last decade have revealed interesting results. In one study using vanadium and molybdenum (Mo) compounds, it was found that their cytotoxicity and efficacy against leukemia cells were similar to those of cisplatin. The vanadium compound [(η⁵-C₅H₅)₂V(5-NH₂-phen)]OTf (V1) was used on human lymphoblastic leukemia MOLT-4 cells and human T-cell leukemia Jurkat cells, showing cytotoxic effects, increased apoptosis through activation of caspases 8 and 9, and elevated levels of p53 and its phosphorylated form [63].

Additionally, in 2019, Ta and colleagues synthesized an amide-imine conjugate compound called PTANAP ((E)-N′-((2-hydroxy naphthalene-1-yl)methylene)-4-methylbenzohydrazide), which was used to make metal compounds with vanadium, copper (Cu), and molybdenum (Mo). These compounds were tested on human leukemia K-562 cells and murine lymphoma 2PK3 cells. The PTANAP- oxidovanadium complex showed the greatest antineoplastic effect, as measured by growth inhibition and cytotoxicity in both cell types. The authors propose that ROS generation and oxidative stress led to DNA damage and apoptosis [64].

Sodium Orthovanadate (SOV) has also been studied for its anticancer effects on hematologic neoplasms. In an in vitro study on acute promyelocytic leukemia cell lines HL-60 and HL-60/A, SOV was shown to inhibit cell proliferation, induce cell cycle arrest at G2/M, and trigger apoptosis. The reported mechanisms included activation of poly-ADP-ribose polymerase (PARP), activation of caspases 3 and 9, disruption of mitochondrial membrane potential, and inhibition of autophagy as promoters of tumor cell death [65]. Another oxidovanadium compound associated with a Schiff base was also tested on HL-60 cells. While administration of either this compound or arsenic trioxide alone-demonstrated cytotoxicity, their co-administration resulted in a greater decrease in cell viability, higher expression of p53 and p21 proteins, and a greater rate of apoptosis. Additionally, co-administration made it possible to reduce the dose of arsenic trioxide, thereby also decreasing its toxic effects, which suggests this strategy as a treatment for acute promyelocytic leukemia [66].

Finally, a vanadium compound derived from 8-formyl-7-hydroxy-4-methyl coumarin was synthesized and functionalized with copper nanoparticles. The vanadyl complex with a tridentate coumarin ligand [VO(CUAP)SO₄] and this complex functionalized with copper nanoparticles [nano Cu-VO (IV)] were tested on breast cancer and leukemia cells. In the case of K-562 leukemia cells, the vanadyl complex had the greatest anticancer effect, inducing cytotoxicity, inhibiting proliferation, and DNA damage [67].

3.5. Skin Cancer

Skin cancer is one of the most prevalent cancers worldwide, with both its incidence and mortality steadily increasing, particularly in regions with a predominantly white population [68]. Among the types of cancers that develop in the skin is melanoma, which, although not the most common form, has increased in global prevalence and is associated with a high mortality rate. It is estimated that 75% of skin cancer-related deaths are due to melanoma, which has shown higher incidence among adolescents and young adults [69]. This cancer type has increased globally at a faster rate than any other malignant neoplasm [70]. This explains why most research on the effects of vanadium has focused on in vivo and in vitro melanoma cell models rather than other types of skin cancers.

In an in vitro study conducted by Rozzo and colleagues, the activity of various vanadium compounds was reported on A375 and CN-mel malignant melanoma cells: NaVO₃ and three oxidovanadium complexes: 1,2-dimethyl-3-hydroxy-4 (1H)-pyridinonate (VS2), 1-methyl-3-hydroxy-4 (1H)-pyridinonate (VS3), and 1-phenyl-2-methyl-3-hydroxy-4 (1H)-pyridinonate (VS4). Evidence indicates that all compounds exhibited antiproliferative activity, while VN and VS2 induced apoptosis and cell cycle arrest [69]. Additionally, the same research group demonstrated that the pro-apoptotic activity of VN and VS2 in these melanoma cells is related to increased ROS production and the consequent inactivation of the MAP kinase (MAPK) pathway [71]. Notably, these compounds were toxic to cancer cells but not to normal fibroblasts under the same conditions.

On the other hand, Das and colleagues evaluated the cytotoxic potential of V₂O₅ nanoparticles in normal cell lines CHO, HEK-293, and NRK-49F and found that cell viability was not affected, suggesting the biocompatibility of these nanoparticles. In some cancer cell lines, such as the murine melanoma B16F10, antiproliferative effects were observed [72]. These findings support the potential of vanadium for therapeutic use without causing harm to non-malignant cells, a result observed in this and other in vitro studies. In the same melanoma cell line, Nivetha and colleagues demonstrated the antiproliferative activity of V₂O₅ nanoparticles and V₂O₅ nanoparticles doped with nickel (Ni@V₂O₅). In the same study, an in vivo model using BALB/c mice showed that intraperitoneal administration of both types of nanoparticles reduced the volume of melanomas generated by B16F10 cells. These findings were associated with vanadium’s interference in the Akt and PI3K signaling pathways [73].

With regard to the Akt pathway, decavanadates have also been tested against melanoma cells. De Sousa-Coelho and colleagues showed that decavanadate (V10) and the metformin–decavanadate complex (Metf-V10) induce dose-dependent antiproliferative activity, reduce cell viability, arrest the cell cycle in G2/M, and increase phosphorylation of signaling proteins ERK and AKT [70].

In 2021, Amante and colleagues conducted a systematic review on vanadium and melanoma. This review includes vanadium compounds and materials such as oxidovanadium(IV), vanadium carbides (MXenes), vanadium pentoxide, vanadyl sulfate, pyridinone-based oxidovanadium(IV) compounds, vanadate, vanadium(IV/V) polysaccharide complexes, binuclear ruthenium(II)-vanadium(IV) complexes, pyridoxal-based oxidovanadium(IV) complexes, and europium-doped yttrium vanadate nanoparticles. This diversity of vanadium-containing molecules was tested on various cancer cell lines and in vivo models (mice), evaluating effects on cell viability, morphology, apoptosis, cell cycle, ROS production, mitochondrial function, protein expression, tumor regression, and survival rate. In general, the tested compounds showed desirable effects against melanoma to varying degrees, both in vitro and in vivo [74].

3.6. Lung Cancer

Lung cancer is the most common type of cancer and the leading cause of cancer-related death worldwide. In 2022, nearly 2.5 million people were diagnosed with lung cancer, with over 1.8 million deaths reported [39].

Numerous in vitro studies using the A549 cell line, derived from pulmonary adenocarcinoma, have demonstrated the anticancer activity of several vanadium compounds. These studies evaluated the cytotoxic effects of V₂O₅ complexes [75], vanadium complexes with pyridoxal-derived ligands [76], as well as complexes synthesized from VOSO₄ with hydrolyzed Cicer arietinum L. protein [77], all of which negatively affected A549 cell viability. In addition to reduced viability, other studies using the same cells and vanadocene complexes reported the induction of apoptosis, cell cycle arrest, and altered expression of proteins involved in regulating these processes [78]. Ribeiro and colleagues observed that oxidovanadium complexes synthesized from benzohydrazones and vanadyl acetylacetonate inhibited cell proliferation, increased cell death, and raised ROS production [79]. Oxidative stress was also elevated following treatment with accessible compounds such as VOSO₄ and NaVO₃, along with decreased viability and induced cell death [80]

Regarding vanadium nanoparticles tested in vitro against lung cancer cells, Liu and colleagues demonstrated that exposing several lung cancer cell lines (EBC-1, LK-2, LU65, LU99, STC 1, and RERF-LC-MA) to vanadium nanoparticles synthesized using Salvia officinalis extract (VNPs@Salvia officinalis) significantly reduced viability, an effect associated with their antioxidant properties [81].

As for in vivo studies, López-Valdez and colleagues [82] evaluated the effect of V₂O₅ inhalation in a model using male CD-1 mice with urethane-induced lung tumors. They observed reduced bronchiolar and alveolar epithelial hyperplasia, smaller and fewer tumors, and a higher apoptosis index in the tumors.

3.7. Nervous System Cancer

According to GLOBOCAN statistics, nervous system cancers rank twelfth in terms of global mortality; however, in children under 14, they are the second leading cause of cancer-related death [39]. Glioblastoma and neuroblastoma are among the most common tumors.

It has been shown that exposing SN56 and SH-SY5Y human neuroblastoma-derived cells to various vanadium compounds produces anticancer effects. On one hand, exposure of SN56 cells to NaVO₃ decreased their viability [83], while exposure of SH-SY5Y cells to SOV [84] and VO(acac)₂ [85] reduced viability, induced apoptotic cell death, and arrested the cell cycle in G2/M and S phases. The authors associated these effects with changes in the expression levels of proteins regulating these processes and increased ROS production. In 2025, Bates and colleagues evaluated the effects of vanadium complexes on T98G human glioblastoma cells, showing impacts on cell proliferation [86].

Other researchers studied the effects of VO(acac)₂ both in vitro and in vivo. In SH-SY5Y neuroblastoma cells and human U251 and murine GL261 glioblastoma cells, Xu and colleagues reported cell cycle changes, energy deficiency, morphological alterations, and activation of methuosis—a form of non-apoptotic cell death. This process was confirmed in vivo in male C57BL/6J mice inoculated with GL261 glioblastoma cells. The authors also reported anti-angiogenic effects through suppression of the HIF-1α factor and tumor growth inhibition in treated mice [87].

3.8. Bone Cancer

Bone cancer is a proliferation of bone cells that appear in any of them, and includes osteosarcoma, Ewing’s sarcoma, and chondrosarcoma. Less than 1% are diagnosed each year and they are associated with significant morbidity and mortality. Osteosarcoma is a type of cancer that begins in the cells that form bones. It usually appears more frequently in children and older adults, and the highest incidence is in the long bones of the legs and also in the arms. It is the most common bone cancer, and because of this it has been the most studied [88].

Studies using vanadium compounds against bone cancer are relatively recent and have demonstrated their effectiveness especially in vitro. The total vanadium content in adults is about 100–200 μg, half of this amount is located in the bones, which are the main long-term storage site, and where vanadate can substitute phosphate in hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂]. Because large amounts of V are detected in bones, the antitumor properties of many compounds of this metal have been widely studied in osteosarcoma [89].

In recent decades, 3D culture models (Multicellular tumor spheroids or 3D bioprinted) have been used to study anticancer effects in bone, both in vitro and in vivo. Thus, León and colleagues reported the effect of the [VO(chrysin)₂ EtOH]₂ (VOchrys) complex, used in other studies, in a mouse osteosarcoma xenograft model. In this study, the human osteosarcoma cell line MG-63 was used; the cells were seeded in 3D multicellular spheroids, and their shape and viability were measured. For the in vivo model, male and female mice (N:NIH(S)-Fox1) were subcutaneously inoculated with MG-63 cells. The results demonstrated antitumor actions of VOchrys in the 3D model, as the shape of the spheroids was altered and their viability decreased; in the in vivo model a significant reduction in tumor volume and suppression of tumor growth were observed, without any symptoms affecting the health or behavior of the animals [90].

The same group investigated the interaction of the oxidovanadium(IV)-clioquinol complex (VO(CQ)₂) with Focal Adhesion Kinase (FAK), which is a tyrosine kinase that plays an important role in adhesion, survival, motility, angiogenesis, and metastasis of cancer cells; this to elucidate the relationship with the regulation of this kinase and the activity of metalloproteinases (MMP), and therefore, to know the antimetastatic effects in the 3D spheroid model of human osteosarcoma cells. For this, the MG-63 cell line was treated with VO(CQ)₂, which was then seeded in 3D multicellular spheroids. Viability and migration of the treated spheroids were determined. The results showed that VO(CQ)₂ reduced migration in the 3D model of human bone cancer cells, as well as the activity of MMP-2 and MMP-9 in a dose-dependent manner [91].

On the other hand, the effectiveness of vanadium nanoparticles has also been tested in vitro. Kalnina and colleagues reported that hydroxyapatite nanoparticles doped with V (V-doped HAPs), prepared by partial substitution of phosphate by vanadate, produced cytotoxic effects in human bone cancer cells SW1353. The authors suggest that this cytotoxicity would be related to the entry of nanoparticles into cancer cells, which requires further studies [92]. Another group explored the effect of nanostructured lipid carriers (NLCs) loaded with the Metvan complex and observed decreased cell viability in the MG-63 line, cytotoxic effects, and apoptosis [93]. These studies demonstrate that vanadium nanoparticles are a feasible option to continue exploring in vivo.

Finally, it is interesting to mention that the use of scaffolds containing vanadium has been explored to examine their anticancer effect, because patients with osteosarcoma present bone defects in the surgical excision zone, which is associated with a high tumor recurrence rate and the survival percentage is only 10%. In an in vivo study with a rat femur with bone defects caused by surgical resection of a tumor, the effect of a V-doped scaffold was explored to simultaneously inhibit osteosarcoma recurrence and promote regeneration of the surgical bone defects. The results showed that tumor cell growth was inhibited and at the same time bone growth in that area was accelerated promoting regeneration [94]. The previous studies demonstrate that there are different strategies using vanadium compounds that are capable of reducing the size of a bone tumor or repairing bone in surgical excision zones, so this research line should be exploited for the benefit of osteosarcoma patients.

Table 2. Biological effects and mechanisms of action exerted by vanadium compounds in vitro.

Cancer Model	Vanadium Compound	Dose/Duration	Biological Effects	Mechanisms	References
MCF-7 Human breast cancer cell line	Vanadium-quercetin complex	125, 200 and 275 μM of V-quercetin complex for 12, 24 and 48 h of treatment	Pro-apoptotic effects	Upregulating p53, caspase 3 and 9, downregulating Akt, mTOR and VEGF expressions and DNA fragmentation	[40]
	Imidazole-based oxidovanadium(IV) complex (VOL).	10–40 µg/mL of VOL for 72 h of treatment	Cytotoxicity	Apoptosis; ROS production, imbalance of catalase and SOD activity; lipid peroxidation.	[43]
	Four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts	0.1–200 µM for the salts for 48 h of treatment	Cytotoxicity, Genotoxicity, cell cycle disruption	DNA cleavage and cell cycle block in the G0/G1 and G2/M phase.	[45]
4T1 Murine breast cancer cell line	NaVO3	1, 10, 50 and 100 μM of NaVO3 for 12, 24 and 48 h of treatment	Proliferation inhibition	Increasing reactive oxygen species (ROS) levels in a concentration-dependent way, arrest cells at G2/M phase, diminish the mitochondrial membrane potential (MMP), promote the progress of apoptosis	[41]
MDA-MB-231 Human breast cancer cell line	Vanadium pentoxide nanoparticles (VnNp)	50 µM of VnNp for 24–48 h of treatment	Ultrastructural alterations, cell death, alterations in cell proliferation and migration.	Increased ROS production and decreased superoxide dismutase (SOD) levels. Cell cycle arrest in the G2/M phase. Apoptosis. Autophagosomes and VnNp are observed in the cytoplasm and mitochondria.	[46]
	Methylimidazole-based oxidovanadium(IV) complex (OVMI)	0, 10, 201 and 30 μg/mL of OVMI for 24 h of treatment	Cytotoxicity, retarded cell proliferation.	ROS-mediated mitochondrial apoptotic death	[44]
MDA-MB-231 and MCF-7. Human breast cancer cell lines	Oxidovanadium compounds (VO1a and VO1b).	MDA-MB-231 cells treated (72 h) with 7.2 µM VO1a or 4.7 µM VO1b; and MCF-7 cells treated (72 h) with 10.7 µM VO1a or 7.3 µM VO1b.	Cytotoxicity Inhibition of multidrug resistance.	Apoptosis cell death. Decreasing ABCG2 transporter activity leads to multidrug resistance and apoptosis.	[42]
HepG2, SK-Hep-1 and Hep3B Human hepatocellular carcinoma cell line	SOV	7.5–30 µM of SOV for 48 h of treatment	Suppression of cell proliferation and cell death	Decreasing Ki67-positive cells, cell cycle arrest at G2/M phase, down-regulation of pro-caspase-9 and 3, increasing cleaved poly(ADP-Ribose) polymerase (PARP) expression, increased apoptosis and inhibition of autophagy	[48]
HepG2 Human hepatocellular carcinoma cell line	NaVO3, Bis(maltolato)-oxidovanadium(IV) (VO(ma)2) and Bis(acetylacetonato)-oxidovanadium(IV) (VO(acac)2)	50, 100 and 400 µM of NaVO3, VO(ma)2 and VO(acac)2 for 4, 8, 12, 16, 24 and 72 h of treatment	Growth inhibition Selectivity of V compounds by tumor cells.	Cell cycle arrest in G1/S phase. Activation of MAPK (ERK) pathway and increase in ROS levels.	[49]
	4-bromo-2-(((5-chloro-2-hydroxyphenyl) imino) methyl) phenol ([IV(L)] complex)	79 and 100 µg/m L of [IV(L)] complex for 24 and 48 h of treatment	Apoptosis and necrosis	Early apoptosis; late apoptosis/necrosis	[50]
Hepa 1-6 Murine hepatoma cell line	Vanadium (V)-iron-oxide (ION) nanoparticle (VIO)	5, 10, 20, 40, 80, 160 and 200 µg/m Lof (VIO) for 24 h of treatment	Cell viability inhibition	Increased levels of ROS, apoptosis and ferroptosis.	[51]
HuH-7.0 Human hepatocellular carcinoma cell line	V2O5 nanoparticles (NPs) and cellulose-coated vanadium oxide NPs.	25, 50, 75 and 100 µg/mL of NPs for 72 h of treatment.	Alteration of cell morphology and decreased viability.	The collapse of the cytoskeleton is proposed.	[52]
HCT-116 Human colorectal carcinoma cell line	Vanadyl N-(2-hydroxyacetophenone) glycinate [VO(NG)2]	20 μg/mL of VO(NG)2 for 24, 48 and 72 h of treatment.	Cell cycle arrest in G2/M and cytotoxicity	Depletion of GSH levels, increasing ROS production, oxidative stress and apoptosis.	[53]
	Zinc Chromium Vanadate nanoparticles (VCrZnO4 NPs)	2.0–75 μg/mL of VCrZnO4 NPs for 48 h of treatment	Cytotoxicity	Apoptosis	[59]
HT-29 Human colorectal carcinoma cell line	Bis(4,7-dimethyl-1,10-phenantroline)sulfatooxidovanadium(IV), Metvan	0.25–5.0 μM of Metvan for 24 h of treatment	Cell viability inhibition	Inhibition of mitochondrial metabolism	[54]
	Na2[VO(silibinin)2 ]· 6H2 O (VOsil) and chrysin [VO(chrysin)2EtOH]2 (VOchrys)	2.5–100 μM of the complexes for 24 and 48 h of treatment.	Cytotoxicity and cell death	Exposure to VOcrhrys caused cell cycle arrest in G2/M. Exposure to VOsil activated caspase 3 and cell apoptosis.	[55]
	Vanadium-luteolin complex	5, 15 and 25 μM of the V-luteolin complex for 24, 36 and 48 h of treatment	Proliferation reduction and cell death. y apoptosis	Apoptosis, activation of p53, Bax, caspase-3 and downregulation of Bcl2 and mTOR/Akt	[57]
CT26 Murine colorectal carcinoma cell line	Flavonoid luteolin and oxidovanadium(IV) complex [VO(lut)(H2O)2]Na3H2O (VOlut)	8.5 μM of VOlut for 5 and 25 h of treatment	Cytotoxicity	The mechanism of action was not explored in the study.	[56]
Caco-2, COLO 320, DLD-1, HCT-15, HCT-116 and HT-29 Human colorectal carcinoma cell lines	Salvia officinalis-based, green-mediated vanadium nanoparticles (VNPs@Salvia officinalis)	100–300 μg/mL of VNPs@Salvia officinalis for 48 h of treatment	Cell viability reduction, cytotoxicity	Antioxidant activity of nanoparticles	[58]
CT26 and MC38 Murine colorectal carcinoma cell line	Vanadium chloride (VCl3)	40 μg/mL of VCl3 for 24 h of treatment	Suppression of cell proliferation	Inhibition of the activity of several enzymes (G6PD, LDH, HK, and PK), blocking glucose metabolism.	[60]
	Vanadium and glutaminase inhibitors (bis 2-(5-phenylacetamido- 1,2,4-thiadiazol-2-yl) ethyl sulfide, BPTES) VSi-BP	40 μg/mL of for 24 h of treatment	Suppression of cell proliferation, reduction in viability and cell death	Inhibition of the activity of several enzymes (G6PD, LDH, HK, and PK), blocking glucose metabolism, apoptosis, decreasing intracellular GSH levels and increasing ROS
MOLT-4 Human acute T-lymphoblastic leukemia cells Jurkat Human T-cell leukemia cells	[(η5-C5H5)2V(5-NH2-phen)]OTf (V1)	1, 2, 3, 5 and 7 μM/L of V1 in MOLT-4 cells for 24, 48 and 72 h of treatment 1, 4, 8, 12 and 20 μM/L V1 in Jurkat cells for 24, 48 and 72 h of treatment	Cytotoxicity, inhibition of proliferation and cell death	Activation of intrinsic and extrinsic apoptosis pathways, with increased levels of caspases 8 and 9. Induction and activation of p53	[63]
K-562 Human leukemia cells 2PK3 Mouse lymphoma cells	(E)-N′-((2-hydroxynaphthalen-1-yl) methylene)-4-methylbenzohydrazide (PTANAP) conjugated with oxidovanadium [V(PTANAP)(μ2-MeO)]2 (V1)	10, 25, 50 and 100 μg/mL of V1 for 24 and 48 h of treatment	Cytotoxicity Inhibition of proliferation, cell death	ROS generation, DNA damage and apoptosis	[64]
HL-60 Acute promyelocytic leukemia cells	SOV	5, 10 and 20 μM of SOV for 72 h of treatment	Cytotoxicity Inhibition of proliferation Cell death	Caspases 3 and 9 activation (mitochondrial apoptosis), activation of poly-ADP-ribose polymerase (PARP). G2/M cell cycle arrest. Inhibition of autophagy, which promotes apoptosis.	[65]
	Schiff base oxidovanadium complex individually or simultaneously administered with arsenic trioxide	1, 10 and 40 μg/mL of Schiff base oxidovanadium complex	Simultaneous exposure to arsenic trioxide: Increased cytotoxicity, cell death	p21 and p53 induction and apoptosis	[66]
K-562 Human leukemia cells	Vanadyl complex [VO(CUAP)SO4] Nano Cu-VO(IV) complex	10, 20, 40 and 80 μg/mL	Cytotoxicity Inhibition of proliferation. The vanadyl complex showed greater anticarcinogenic effect.	ROS generation and DNA damage	[67]
A375 and CN-mel Malignant melanoma cell lines	NaVO3 and three oxidovanadium complexes (VS2, VS3 and VS4).	10 and 20 μM of VN and the three complexes for 24, 48 h and 72 h of treatment	Antiproliferative activity and cytotoxicity	Apoptosis induction and cell cycle arrest in G2/M phase	[69]
	NaVO3 and oxidovanadium complex [VO(dhp)2] VS2	10 and 20 μM of VN and VS2 complex for 24, 48 h and 72 h of treatment	Cell death	Increasing ROS levels, inactivation of the MAPK pathway, increased p21Cip1 inhibitor and apoptosis	[71]
B16F10 Murine melanoma cell line	Vanadium pentoxide nanoparticles (V2O5 NPs 30–60 nm)	1–50 μg mL of V2O5 NPs	Antiproliferative activity	Generation of intracellular ROS, increased p53, and decreased survivin in cancer cells	[72]
	Vanadium pentoxide nanoparticles (V2O5 NPs) and nickel doped vanadium pentoxide nanoparticles (Ni@V2O5 NPs)	V2O5 (0–40 μg/mL) and Ni@V2O5 (0–20 μg/mL) for 24 h of treatment	Proliferation inhibition and cytotoxicity	Mitochondrial ROS generation, mitochondrial and nuclear damage, apoptosis	[73]
UACC-62 Human melanoma cell line	Decavanadate (V10) and metformin-decavanadate (Metf-V10)	0 and 20 μM of V10 and Metf-V10 for 24, 48 and 72 h of treatment	Decrease in cellular viability and antiproliferative effects.	Cell cycle arrest in G2/M phase, ERK and AKT signaling pathways hyperactivation	[70]
A549 Human lung adenocarcinoma cell line	Organometallic complexes of vanadocene with N,N′-chelating ligands	1–60 μM complexes for 24, 48 and 72 h of treatment	Cytotoxicity and antiproliferative activity in a dose dependent manner	Apoptosis mediated by activation of caspase-8,-3 and-7. G2 and S phase cell cycle arrest, modification in the expression of proteins that regulate the cell cycle such as: Chk1, Chk2, ERK1/2 and p21.	[78]
	VOSO4 and NaVO3	0–100 µM of VOSO4 and NaVO3 for 24 and 48 h of treatment	Cell death and inhibition of proliferation	Increasing in ROS production.	[80]
	Vanadyl sulfate complexes with Cicer arietium L. (CPH-V Complexes)	1–30 µg/mL of CPH-V Complexes for 48 h of treatment	Antiproliferative activity in a concentration dependent manner	Cell growth inhibition	[77]
	Bis(μ-oxido)-bridged vanadium(V) dimer with a Schiff base ligand (pedf) [(VVO2)2(pedf)2]	2–80 µg/m L of [(VVO2)2(pedf)2] for 24 h of treatment	Antiproliferative activity in a concentration dependent manner, decreased cell viability and DNA damage.	Loss of membrane integrity, DNA cleavage and apoptosis regulated by modification in p53, PPAR and PCNA expression	[75]
	Vanadium complexes with pyridoxal-derived ligands	0.1–500 µM for 24 h of treatment	Antiproliferative activity in a concentration dependent manner	The mechanism of action was not explored in the study.	[76]
	Oxidovanadium(IV) complexes	0.78–50 µM for 24 h of treatment	Decreased cell viability and concentration-dependent antiproliferative activity	Apoptosis mediated by activation of caspase-3 and -7. Increased ROS.	[79]
SN56 Murine neuroblastoma cell line	NaVO3	50–200 µM for 1 h of treatment	Concentration-dependent decrease in viability and morphological changes	Loss of membrane integrity. Loss of cellular arborization, resulting in a rounded structure with vacuoles inside.	[83]
SH-SY5Y Human neuroblastoma cell line	SOV	0.05–50 µM of SOV for 24, 48 and 72 h of treatment.	Concentration- and time-dependent cell death. Reduction in cell proliferation.	Apoptosis associated with reduced Bcl-2 protein expression. Cell cycle arrest in G2/M and S phase and inhibition of PIWIL2.	[84]
	Bis(acetylacetonato) oxidovanadium(IV) ([VO(acac)2])	12.5–400 µM of [VO(acac)2] for 24 and 48 h of treatment.	Concentration- and time-dependent cell death. Cell cycle dysregulation	Increased ROS production and cell apoptosis. Arrest in different cell cycle phases associated with Cyclin D1 levels, expression in GSK-3 β, Akt/PKB and Rb phosphorylation levels.	[85]
SH-SY5Y Human neuroblastoma cell line U251 Human glioblastoma cell line GL261 Murine glioblastoma cell line		2–16 µM of (VO(acac)2) for 24 h of treatment	Inhibitory effect on concentration-dependent cell viability, cell cycle suppression, micropinocytosis-derived cytoplasmic vacuole formation, energy deficiency and cell death.	Decreased cell viability, cell cycle arrest in the G2/M phase, low intracellular ATP levels, a decrease in mTOR and P70S6K and an increase in AMPK. Death by the process of Metuosis upon initiation of Rac-MKK-JNK pathway activation.	[87]
T98G Human glioblastoma cell line	Oxidovanadium(IV) Schiff base–catecholate complex [VO(3-tBuHSHED)(TIPCAT)]	0.1–100 µM of [VO(3-tBuHSHED)(TIPCAT)] for 24 and 72 h of treatment	Decreased cell viability. Concentration-dependent antiproliferative effect.	The mechanism of action was not explored in the study.	[86]
MG-63 Human Osteosarcoma cell line	Oxidovanadium with flavonoid chrysin [VO(chrysin)2 EtOH]2 (VOchrys)	Multicellular spheroids treated with 100 µM of VOchrys for 72 h of treatment.	Cytotoxicity affecting the shape and volume of the spheroids	The mechanism of action was not explored in the study.	[90]
	4,7-dimethyl-1,10-phenathroline 7 sulphatooxidovanadium(IV) nanostructured lipid carriers (NLCs Mv)	25 μM and 50 μM of NLCs Mv for 24 h of treatment	Reduction in cell viability and cytotoxicity.	Apoptosis	[93]
	Oxidovanadium(IV) -clioquinol complex VO(CQ)2	2.5–10 µM of VO(CQ) for 24 h of treatment	Inhibition of cell migration	Reduced activity of MMP-2 and MMP-9.	[91]
SW1353 Human osteosarcoma	Vanadium-doped nanocrystalline hydroxyapatite V-doped HAP nanoparticles	5.0 mg/mL of V-doped HAP nanoparticles for 72 h of treatment	Cytotoxicity	The mechanism of action was not explored in the study.	[92]

and

Table 3. Biological effects and mechanisms of action exerted by vanadium compounds in vivo.

Cancer Model	Vanadium Compounds	Route/Dose/Duration	Biological Effects	Mechanisms	References
DMBA breast cancer model in female Sprague-Dawley rats	Vanadium-quercetin complex	Oral administration, 20 mg/kg of body mass with V-quercetin complex (1 dose per day for 24 weeks).	Inhibition of the development of mammary lesions in rats treated with the complex.	Increased apoptotic index, p53 and Bax; decreased proliferation.	[40]
Breast cancer model 4T1-induced mammary tumors in female Balb/c mice	Sodium metavanadate (NaVO3)	Intraperitoneal administration of 10, 15 and 20 mg/Kg of body mass with NaVO3 (1 dose per day for three weeks).	Decrease in tumor volume, less development of microvasculature.	Inhibition of tumor growth and increased death by apoptosis. Increase in ROS.	[41].
	Methylimidazole-based oxidovanadium(IV) complex (OVMI)	Intravenously administration of 10, 20 and 30 mg/kg of body mass with OVMI (Once 72 h after the previous injection for a range of 16 days.	Size and volume tumor size reduction. Antimetastatic activity.	Decreasing cell proliferation and Ki67 expression, apoptosis and decreased metastasis markers (E-cadherin and N-cadherin).	[44].
Orthotopic Hepatocellular carcinoma model in male nude BALB/C mice	Sodium orthovanadate (SOV)	Intraperitoneal administration of 10, 15 and 20 mg/Kg of body mass with SOV (1 dose per day for three weeks).	Decrease in tumor volume, and inhibition of tumor growth, less development of microvasculature.	Suppression of cell proliferation, decreasing Ki67-positive cells, inhibition of autophagy.	[48]
CT26 Liver metastasis model in BALB/C mice	Flavonoid luteolin and oxidovanadium(IV) complex [VO(lut)(H2O)2]Na3H2O (VOlut)	Intravenously administration of 20 mg/kg of body mass with VOlut.	No evidence of metastatic nodules in the liver	The mechanism of action was not explored in the study.	[56]
DMH colorectal cancer model in male Wistar rats	Vanadium-luteolin complex	Via oral gavage commencing the day after DMH injection and continued for 18 weeks.	Reduction in the formation of aberrant crypt foci and cell death.	Increasing in p53 and Bax expressions, Bcl2, apoptosis. Elevation of SOD, CAT, and glutathione levels	[57]
Mouse melanoma in female C57BL/6J mice implanted with the B16F10 cell cancer line	Vanadium pentoxide nanoparticles (V2O5 NPs 30–60 nm)	Intraperitoneal administration of 10 and 20 mg of V2O5 NPs (7 consecutive doses during 28 days).	Improved survival of melanoma tumor-bearing C57BL6/J mice and showed no toxic effects in treated animals.	Tumoral angiogenesis inhibition.	[72]
	Vanadium pentoxide nanoparticles (V2O5 NPs) and Ni doped vanadium pentoxide nanoparticles (Ni@V2O5 NPs)	Intraperitoneal administration of 100 mg/kg of V2O5 NPs and 50 mg/kg of Ni@V2O5 NPs (1 dose per day for 28 days).	Reduction in the volume of melanomas generated	Increased expression of Akt and PI3K interfering with this signaling pathway.	[73]
Urethane lung cancer model in male CD-1 mice	Vanadium pentoxide (V2O5)	Inhalation administration of 1.56 mg V/m3 of V2O5 (twice a week, for 8 weeks).	Decreased tumor size, increased cell death.	Increase in the apoptotic index in terminal deoxynucleotidyl transferase-labeled tumor cells, which reduced the number and size of tumors	[82]
Murine glioblastoma GL261 induced tumors in male C57BL/6J mice	Bis(acetylacetonato)oxidovanadium(IV) (VO(acac)2)	Intratumoral injection of 10 and 25 μmol/kg VO(acac)2 (1 dose daily for 14 days).	Inhibition of tumor growth, inhibition of angiogenesis and tumor ischemia.	Suppression of HIF-1α levels, formation of vacuoles in tumor tissues leading to death via Metuosis.	[87]
Osteosarcoma cell xenograft in females and males N:NIH (S) Fox1nu mice	Oxidovanadium with flavonoid chrysin [VO(chrysin)2 EtOH]2 (VOchrys)	Intraperitoneal administration of 27.5 mg/kg of body mass with VOchrys.	Decreased tumor volume in a concentration dependent manner.	The mechanism of action was not explored in the study.	[90]
Osteosarcoma cell xenograft in male SD rats injected with UMR-106 cancer cells.	Vanadium-doped mesoporous bioactive glass (V(IV/V)-MBG)	The V(IV/V)-MBG scaffold was implanted in the tumor excision area and euthanized at 4 and 8 weeks.	Inhibition of tumor cell growth and promotion of normal bone in the tumor excision site.	Increased ROS generation. The continued release of V(IV) and V(V) significantly promoted osteogenesis.	[94]

summarize the findings on the antineoplastic effects found in the most common and most widely studied types of cancer. However, other cell lines from less common neoplasias have been studied, which are discussed further on.

4. Anticancer Effects in Other Types of Cancer

The effects of V compounds as anticancer agents have been tested in vitro in other types of cancer that have not been previously addressed due to limited studies; these include stomach, pancreatic, cervical, and ovarian cancers, among others.

Regarding stomach cancer, vanadium compounds have been tested in different human gastric cancer cell lines. Ling and colleagues explored the effect of 19 vanadium complexes on four cancer cell lines: MGC-803 human gastric cancer, EC109 esophageal adenocarcinoma, MCF7 breast cancer, and HepG2 hepatic carcinoma. The authors reported the antiproliferative and pro-apoptotic activity of the complexes against these cells, with a preference for MGC-803; in these cells, the expression of Bax, PARP, and caspases 3/9 increased while Bcl2 decreased [95]. In another study, it was demonstrated that the oxidovanadium complex with the Schiff base phenylenediamine ([N,N’-bis (3-methoxy-salicylidene) -1,2-phenylenediamine] V(IV)) in the MKN95 cell line reduced proliferation and cell migration and increased cell death. When analyzing the effect on the cell cycle, the authors observed that the complex arrested the cycle in G2/M, which could be explained by the increase in the expression of p53 and GADD45 and the decrease in CDC25 [96]. On the other hand, Wang and colleagues analyzed the effects of exposure to SOV in vitro and in vivo. They demonstrated that exposure to this compound inhibits cell proliferation, increases the sensitivity to radiotherapy of SGC-7901 and MGC-803 human gastric cancer cells, and tumors induced in a xenograft model in female mice subcutaneously injected with SGC-7901 cells. Another effect observed in this model was that SOV inhibits radiation-induced autophagy, preventing cells from becoming resistant to radiotherapy [97].

Another type of cancer whose relationship with the anticancer effect of vanadium compounds has been little explored is pancreatic cancer. This type of cancer is one of the most difficult to treat, so new therapeutic agent alternatives, such as vanadium compounds, are continuously sought because current options have shown little effectiveness. Wu and colleagues investigated the effect of NaVO₃ and VO(acac)₂ on the human pancreatic cancer cell line AsPC-1, demonstrating that both compounds induce cell cycle arrest in G2/M by activation of the PI3K/AKT and MAPK/ERK pathways, increase in production and reduced glutathione (GSH) [98]. In another study, similar results were found in the PANC-1 pancreatic ductal adenocarcinoma cell line when independently exposed to 7 V compounds: C1-VOSO₄, C2- oxydiacetate-VO complex, C3 and C4 with coupled organic ligands (phenanthroline and bipyridine), C5-C7 with organic ligands phenanthroline, bipyridine, and 4-amino-2-methylquinoline bound as counterions. The results demonstrated cytotoxicity, inhibition of autophagy, cell cycle arrest in G2/M associated with mitotic catastrophe induction, and elevation in ROS levels [99]. Other results from the same group showed the effect of three oxidovanadium(IV) complexes with 2-amino-3-hydroxypyridine against the PANC-1 and MIA PaCa2 cell lines; cytotoxicity, increased ROS production, disruption of mitochondrial membrane potential, and apoptosis were reported [100]. Finally, Griffin and colleagues reported the antiproliferative and cytotoxic activity (by apoptosis or necrosis) of the complex (NH₄)[V(dtbc)₃] on PANC-1 cells [101].

Regarding cervical cancer, anticancer effects have also been shown. This type of cancer has high incidence and mortality worldwide in women, so it is necessary to explore more therapeutic options to treat it. One study reported the effect of two vanadium complexes coupled with nicotyl hydrazone, OVK89 and OVK49, on human cervical adenocarcinoma cells SiHa and HeLa, which are also positive for Papilloma virus. The results showed that both compounds are capable of inducing cell death by apoptosis by altering the mitochondrial membrane potential and inducing p53, especially in SiHa cells. It is important to mention that this is the first study demonstrating that vanadium compounds can induce p53-dependent apoptosis in Papilloma virus-positive cancers [102]. In another work, on the same cells, it was shown that other vanadium complexes coupled to diketones exhibit cytotoxic activity by activating apoptosis. In silico data provided in this work show the ability of these complexes to bind to DNA and fragment it, behaving as powerful cytotoxics [103]. On the other hand, the bis(triethylammonium) tris [1,1-bis(indol-3-yl)-1-(3,4-catecholate) methane] vanadate (IV) complex has shown promising results; significant antiproliferative activity, a strong capacity to bind DNA, mitochondrial damage, increased ROS formation, and cell cycle arrest in G2/M in ACC-149 cells derived from HeLa [104].

In vivo, the effect of vanadium complexes in cervical cancer has been little studied. Bai and colleagues demonstrated that the oxidovanadium complex coupled to thiosemicarbazones VO-2-hydroxy-1-naphthaldehyde thiosemicarbazone (hntdtsc) 2-(4-nitrophenyl)-imidazo [4,5-f]1,10-phenanthroline (NPIP) exerted significant antiproliferative effect on HeLa cell cultures by arresting the cycle in G0/G1 phase with increased expression of p16 and decreased cyclin D1, CDK4, and p-Rb, increased ROS and apoptosis measured by mitochondrial damage. In vivo the results coincided with those found in vitro: the complex suppressed growth and inhibited tumor progression, which is related to the detected decrease in Ki67 nuclei staining; it also induced apoptosis and increased caspase 3 expression in a xenograft model in nude mice [105].

To conclude this section, ovarian cancer is addressed. Reytman and colleagues demonstrated the cytotoxic activity of six oxidovanadium complexes coupled with phenolate (LpVO) on various cancer cell lines, including A2780 and OVCAR-3 ovarian carcinoma [106]. On the other hand, it has been found that treatment with V₂O₅ triggers a potent antiproliferative effect in different cell lines including A2780 [107]. In both cases, more studies are required to elucidate their mechanisms of action. Below, the main mechanisms of action induced by vanadium compounds that have been identified are summarized.

5. Conclusions

Vanadium is a metal capable of regulating various biological functions, as evidenced in numerous studies, for which it has been attributed pharmacological properties such as insulin-mimetic, antihyperlipidemic, antihypertensive, and, of course, antineoplastic properties [22,36]. In recent decades, studies exploring the anticancer effect of vanadium have increased exponentially, since the coordination capacity of this metal has allowed the development of a diversity of compounds, which is important given that it opens the possibility of numerous treatment options against the cancer types with the highest incidence and mortality rates worldwide. Vanadium compounds have proven to be viable and useful options for the elimination of cancer cells in in vitro studies, while in vivo models have reaffirmed the possibility of using them as treatments, although these latter studies are scarce.

Experimental evidence has demonstrated that vanadium compounds have desirable effects to combat numerous types of cancer by activating diverse mechanisms of action through which they exert their antitumor action, as summarized in Figure 1 and Figure 2. These include the induction of oxidative stress, DNA damage, cell cycle arrest, induction of apoptosis, and regulation of the autophagy process, among the most important mechanisms.

As outlined in Table 1, there are several advantages to utilizing alternative metal complexes to Pt as anticancer agents, some of which are analogous to those exhibited by V compounds, including their respective mechanisms of action. In comparison to platinum, they are less toxic and tend to be more selective in their action, targeting cancer cells with greater precision. In comparison to V, it offers the advantage that its mechanisms of action have been the subject of more extensive study, and a limited number of studies have examined the in vivo applicability of these metals’ compounds.

An important point to consider when analyzing the results of different studies to determine the action mechanisms is that compounds with vanadium ions are quite labile, and interconversion between V^IV and V^V occurs easily. The V compounds, once dissolved in water containing solvents and at low concentrations (as those typically used in therapeutic applications) almost never maintain their integrity. In vitro, it is well known that the reactions of V complexes with components of the culture medium influence the observed biological activity; however, only a few studies have documented the speciation of V complexes once incorporated into the incubation medium [108].

In an interesting study conducted by Nunes and colleagues, it was demonstrated that the three V^IVO complexes used as cytotoxic agents—formulated as [V^IVO(OSO₃)(phen)₂] (1) (phen = 1,10-phenanthroline), [V^IVO(OSO₃)(Me₂phen)₂] (2) (Me₂phen = 4,7-dimethyl-1,10-phenanthroline), and [V^IVO(OSO₃)(amphen)₂] (3) (amphen = 5-amino-1,10-phenanthroline)—underwent hydrolysis, and most of the V^IV was oxidized to different V^V species. The authors further indicated that when lower concentrations of the complexes were added to the culture medium, hydrolysis occurred, and the V^IV species and those containing phenanthroline (phen) remain bound primarily to serum albumin in the medium, whereas at higher concentrations, the complexes persisted for longer periods. Therefore, the mechanisms of action exerted are closely related to the concentration of the complexes used [109].

In another review, Pessoa and Correia provide an in-depth discussion of the chemical changes (hydrolysis, ligand exchange, and redox reactions) undergone by V complexes, emphasizing the importance of evaluating speciation to better understand their mechanisms of action and to attribute them to the correct species [110]. A particularly relevant point highlighted in this work is the significance of these chemical changes in the compounds when used at low concentrations, such as those employed in biological assays, making their consideration essential.

On the other hand, in vivo studies are expected to show behavior similar to what has been reported in vitro; however, this outcome is not guaranteed. A specific compound will undergo various chemical transformations both before administration and afterward, until it reaches its target organ. It is therefore of vital importance to understand these transformations before proposing a compound as a treatment and advancing to preclinical phases [111,112]. Dinda and colleagues provide a comprehensive description of these changes in V complexes used in different studies, detailing the compounds formed in solution as well as the transformations that would occur under experimental conditions, aiming to guide the reader toward determining the speciation of their compounds and thereby more accurately proposing those whose biological activity could be potentially beneficial [112].

One approach currently under consideration to address changes in the speciation of metal complexes is the use of nanoparticles or encapsulation methods. An example is provided by the studies conducted by Sakurai and colleagues, who reported that ECC encapsulation of V^IVOSO₄ for oral administration to experimental rats increased the bioavailability and absorption of the complex. Their findings indicated that these capsules passed through the digestive tract intact, reaching the small intestine, where they released V^IVOSO₄ directly into this organ [113,114,115].

It is important to mention that most of the studies reported in the literature on the anticancer potential of V complexes do not include an analysis regarding these aspects of speciation, which represents an important challenge that should be considered in future research.

Figure 1 and Figure 2 provide a general summary of the mechanisms of action exerted by V complexes, both in animal models and in vitro studies. ROS production and the resulting oxidative stress are thought to be one of the main ways in which the metal acts. ROS can function as intracellular messengers that have the ability to participate in different signaling pathways, such as proliferation, differentiation, apoptosis, etc., promoting the elimination of cancer cells. It is interesting to note that both figures show the activation of apoptosis, as well as alterations in the mechanisms of autophagy and proliferation, which ultimately lead to the death of transformed cells [26,28,32,34,35].

As highlighted above, especially in the context of in vitro studies, several of the compounds used exert their cytotoxic actions particularly on cancer cells and not on normal cells; in in vivo models, the compounds did not show toxic effects in the experimental organisms. These aspects stand as advantages of vanadium compounds as anticancer agents due to their preference for malignant cells, which could reduce adverse effects generated by chemotherapeutic treatment, and represent an excellent alternative to platinum compounds, which remain the most widely used.

It is important to highlight that most vanadium compounds with anticancer potential have been tested, especially in vitro; their study in animal models still needs to be expanded, and, if the benefit is considered greater than toxicity, clinical trials could allow their use as treatments in the future. For the moment, the results appear promising.

Finally, another benefit is that it has also been seen that vanadium compounds exert cytotoxic mechanisms in cells that have been identified as resistant to platinum treatment, so in the near future, it is necessary to explore the effects of vanadium compounds, especially in vivo, to have a broader perspective of what could occur in the whole organism.