Vanadium Compounds with Antidiabetic Potential.

Over the last four decades, vanadium compounds have been extensively studied as potential antidiabetic drugs. With the present review, we aim at presenting a general overview of the most promising compounds and the main results obtained with in vivo studies, reported from 1899-2023. The chemistry of vanadium is explored, discussing the importance of the structure and biochemistry of vanadate and the impact of its similarity with phosphate on the antidiabetic effect. The spectroscopic characterization of vanadium compounds is discussed, particularly magnetic resonance methodologies, emphasizing its relevance for understanding species activity, speciation, and interaction with biological membranes. Finally, the most relevant studies regarding the use of vanadium compounds to treat diabetes are summarized, considering both animal models and human clinical trials. An overview of the main hypotheses explaining the biological activity of these compounds is presented, particularly the most accepted pathway involving vanadium interaction with phosphatase and kinase enzymes involved in the insulin signaling cascade. From our point of view, the major discoveries regarding the pharmacological action of this family of compounds are not yet fully understood. Thus, we still believe that vanadium presents the potential to help in metabolic control and the clinical management of diabetes, either as an insulin-like drug or as an insulin adjuvant. We look forward to the next forty years of research in this field, aiming to discover a vanadium compound with the desired therapeutic properties.

Targeting Breast Cancer and Their Stem Cell Population through AMPK Activation: Novel Insights.

Despite some significant advancements, breast cancer has become the most prevalent cancer in the world. One of the main reasons for failure in treatment and metastasis has been attributed to the presence of cancer initiating cells-cancer stem cells. Consequently, research is now being focussed on targeting cancer cells along with their stem cell population. Non-oncology drugs are gaining increasing attention for their potent anticancer activities. Metformin, a drug commonly used to treat type 2 diabetes, is the best example in this regard. It exerts its therapeutic action by activating 5' adenosine monophosphate-activated protein kinase (AMPK). Activated AMPK subsequently phosphorylates and targets several cellular pathways involved in cell growth and proliferation and the maintenance of stem-like properties of cancer stem cells. Therefore, AMPK is emerging as a target of choice for developing effective anticancer drugs. Vanadium compounds are well-known PTP inhibitors and AMPK activators. They find extensive applications in treatment of diabetes and obesity via PTP1B inhibition and AMPK-mediated inhibition of adipogenesis. However, their role in targeting cancer stem cells has not been explored yet. This review is an attempt to establish the applications of insulin mimetic vanadium compounds for the treatment of breast cancer by AMPK activation and PTP1B inhibition pathways.

Alzheimer's Disease and Diabetes Mellitus in Comparison: The Therapeutic Efficacy of the Vanadium Compound.

Alzheimer's disease (AD) is an intractable neurodegenerative disease that leads to dementia, primarily in elderly people. The neurotoxicity of amyloid-beta (Aß) and tau protein has been demonstrated over the last two decades. In line with these findings, several etiological hypotheses of AD have been proposed, including the amyloid cascade hypothesis, the oxidative stress hypothesis, the inflammatory hypothesis, the cholinergic hypothesis, et al. In the meantime, great efforts had been made in developing effective drugs for AD. However, the clinical efficacy of the drugs that were approved by the US Food and Drug Association (FDA) to date were determined only mild/moderate. We recently adopted a vanadium compound bis(ethylmaltolato)-oxidovanadium (IV) (BEOV), which was originally used for curing diabetes mellitus (DM), to treat AD in a mouse model. It was shown that BEOV effectively reduced the Aß level, ameliorated the inflammation in brains of the AD mice, and improved the spatial learning and memory activities of the AD mice. These finding encouraged us to further examine the mechanisms underlying the therapeutic effects of BEOV in AD. In this review, we summarized the achievement of vanadium compounds in medical studies and investigated the prospect of BEOV in AD and DM treatment.

Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1G93A) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1G93A motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1G93A mice intraperitoneally daily with 400 µg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1G93A mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1G93A and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.

Vanadium-based nanomaterials for cancer diagnosis and treatment.

In the past few decades, various vanadium compounds have displayed potential in cancer treatment. However, fast clearness in the body and possible toxicity of vanadium compounds has hindered their further development. Vanadium-based nanomaterials not only overcome these limitations, but take advantage of the internal properties of vanadium in photics and magnetics, which enable them as a multimodal platform for cancer diagnosis and treatment. In this paper, we first introduced the basic biological and pharmacological functions of vanadium compounds in treating cancer. Then, the synthesis routes of three vanadium-based nanomaterials were discussed, including vanadium oxides, 2D vanadium sulfides, carbides and nitrides: VmXn (X = S, C, N) and water-insoluble vanadium salts. Finally, we highlighted the applications of these vanadium-based nanomaterials as tumor therapeutic and diagnostic agents.

A Short-Lived but Highly Cytotoxic Vanadium(V) Complex as a Potential Drug Lead for Brain Cancer Treatment by Intratumoral Injections.

The chemistry and short lifetimes of metal-based anti-cancer drugs can be turned into an advantage for direct injections into tumors, which then allow the use of highly cytotoxic drugs. The release of their less toxic decomposition products into the blood will lead to decreased toxicity and can even have beneficial effects. We present a ternary VV complex, 1 ([VOL1 L2 ], where L1 is N-(salicylideneaminato)-N'-(2-hydroxyethyl)ethane-1,2-diamine and L2 is 3,5-di-tert-butylcatechol), which enters cells intact to induce high cytotoxicity in a range of human cancer cells, including T98g (glioma multiforme), while its decomposition products in cell culture medium were ≈8-fold less toxic. 1 was 12-fold more toxic than cisplatin in T98g cells and 6-fold more toxic in T98g cells than in a non-cancer human cell line, HFF-1. Its high toxicity in T98g cells was retained in the presence of physiological concentrations of the two main metal-binding serum proteins, albumin and transferrin. These properties favor further development of 1 for brain cancer treatment by intratumoral injections.

Vanadium and insulin: Partners in metabolic regulation.

Since the 1970s, the biological role of vanadium compounds has been discussed as insulin-mimetic or insulin-enhancer agents. The action of vanadium compounds has been investigated to determine how they influence the insulin signaling pathway. Khan and coworkers proposed key proteins for the insulin pathway study, introducing the concept "critical nodes". In this review, we also considered critical kinases and phosphatases that participate in this pathway, which will permit a better comprehension of a critical node, where vanadium can act: a) insulin receptor, insulin receptor substrates, and protein tyrosine phosphatases; b) phosphatidylinositol 3'-kinase, 3-phosphoinositide-dependent protein kinase and mammalian target of rapamycin complex, protein kinase B, and phosphatase and tensin homolog; and c) insulin receptor substrates and mitogen-activated protein kinases, each node having specific negative modulators. Additionally, leptin signaling was considered because together with insulin, it modulates glucose and lipid homeostasis. Even in recent literature, the possibility of vanadium acting against metabolic diseases or cancer is confirmed although the mechanisms of action are not well understood because these critical nodes have not been systematically investigated. Through this review, we establish that vanadium compounds mainly act as phosphatase inhibitors and hypothesize on their capacity to affect kinases, which are critical to other hormones that also act on common parts of the insulin pathway.

Vanadium coordination compounds loaded on graphene quantum dots (GQDs) exhibit improved pharmaceutical properties and enhanced anti-diabetic effects.

Vanadium compounds are promising anti-diabetic agents, and graphene quantum dots (GQDs) are emerging as potential drug delivery systems to improve drug solubility in water and membrane transport. Using highly dispersible and water-soluble GQDs, we herein prepared a novel GQD-VO (p-dmada) complex, in which vanadium coordination compounds [VO(p-dmada)] were packed closely on one side of the GQD sheets possibly via the π-π stacking mechanism. The in vitro tests showed that GQD-VO(p-dmada) exhibited membrane permeability (Papp) as good as that of GQDs with reduced cytotoxicity. In vivo tests on type 2 diabetic mice demonstrated that GQD-VO(p-dmada) exhibited a delayed glucose lowering profile but more profound effects on insulin enhancement and ß-cell protection after three-week treatment compared to VO(p-dmada) alone. In addition, GQD alone was observed for the first time to effectively lower the blood lipid levels of the db/db mice. Overall, GQD-VO(p-dmada) showed improved pharmacokinetic performance and hypoglycemic effects, and using GQD as a nanoplatform for drug delivery may provide vast opportunities for the further design of metal-based pharmaceutical agents.

Green synthesis of ultra-small VOx nanodots for acidic-activated HSP60 inhibition and therapeutic enhancement.

Using metal oxide semiconductor nanomaterials for synergistic cancer treatment has recently attracted the attention of numerous researchers. Herein, oxygen-defective vanadium oxide nanodots (VOx NDs) with ultra-small size and great dispersibility were synthesized via a novel user-friendly method, and then doxorubicin was loaded onto the VOx NDs surfaces. The VOx NDs had great photothermal conversion efficiency and stability. Doxorubicin-loaded VOx NDs can simultaneously serve as therapeutic agent and tumor microenvironment-activable HSP60 inhibitor, resulting in improved efficacy of photothermal therapy and released active doxorubicin for chemotherapy. Finally, we show that synergistic treatment achieved significant therapeutic effects in mice. These results provided a promising strategy for developing novel methods of synthesizing metal oxide semiconductors for enhanced synergistic cancer treatment.

Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus.

Vanadium compounds have been primarily investigated as potential therapeutic agents for the treatment of various major health issues, including cancer, atherosclerosis, and diabetes. The translation of vanadium-based compounds into clinical trials and ultimately into disease treatments remains hampered by the absence of a basic pharmacological and metabolic comprehension of such compounds. In this review, we examine the development of vanadium-containing compounds in biological systems regarding the role of the physiological environment, dosage, intracellular interactions, metabolic transformations, modulation of signaling pathways, toxicology, and transport and tissue distribution as well as therapeutic implications. From our point of view, the toxicological and pharmacological aspects in animal models and humans are not understood completely, and thus, we introduced them in a physiological environment and dosage context. Different transport proteins in blood plasma and mechanistic transport determinants are discussed. Furthermore, an overview of different vanadium species and the role of physiological factors (i.e., pH, redox conditions, concentration, and so on) are considered. Mechanistic specifications about different signaling pathways are discussed, particularly the phosphatases and kinases that are modulated dynamically by vanadium compounds because until now, the focus only has been on protein tyrosine phosphatase 1B as a vanadium target. Particular emphasis is laid on the therapeutic ability of vanadium-based compounds and their role for the treatment of diabetes mellitus, specifically on that of vanadate- and polioxovanadate-containing compounds. We aim at shedding light on the prevailing gaps between primary scientific data and information from animal models and human studies.