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1.
Pharmaceuticals (Basel) ; 17(1)2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38275998

RESUMO

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

2.
J Inorg Biochem ; 236: 111952, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36049257

RESUMO

Plasma membrane calcium ATPases (PMCA) and sarco(endo) reticulum calcium ATPases (SERCA) are key proteins in the maintenance of calcium homeostasis. Herein, we compare for the first time the inhibition of SERCA and PMCA calcium pumps by several polyoxotungstates (POTs), namely by Wells-Dawson phosphotungstate anions [P2W18O62]6- (intact, {P2W18}), [P2W17O61]10- (monolacunary, {P2W17}), [P2W15O56]12- (trilacunary, {P2W15}), [H2P2W12O48]12- (hexalacunary, {P2W12}), [H3P2W15V3O62]6- (trivanadium-substituted, {P2W15V3}) and by Preyssler-type anion [NaP5W30O110]14- ({P5W30}). The speciation in the solutions of tested POTs was investigated by 31P and 51V NMR spectroscopy. The tested POTs inhibited SERCA Ca2+-ATPase activity, whereby the Preyssler POT showed the strongest effect, with an IC50 value of 0.37 µM. For {P2W17} and {P2W15V3} higher IC50 values were determined: 0.72 and 0.95 µM, respectively. The studied POTs showed to be more potent inhibitors of PMCA Ca2+-ATPase activity, with lower IC50 values for {P2W17}, {P5W30} and {P2W15V3}.


Assuntos
Cálcio , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Cálcio/química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
3.
J Inorg Biochem ; 235: 111915, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35834898

RESUMO

Decavanadate is a polyoxometalate (POMs) that has shown extensive biological activities, including antidiabetic and anticancer activity. Importantly, vanadium-based compounds as well as antidiabetic biguanide drugs, such as metformin, have shown to exert therapeutic effects in melanoma. A combination of these agents, the metformin-decavanadate complex, was also recognized for its antidiabetic effects and recently described as a better treatment than the monotherapy with metformin enabling lower dosage in rodent models of diabetes. Herein, we compare the effects of decavanadate and metformin-decavanadate on Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from rabbit skeletal muscles and on cell signaling events and viability in human melanoma cells. We show that unlike the decavanadate-mediated non-competitive mechanism, metformin-decavanadate inhibits Ca2+-ATPase by a mixed-type competitive-non-competitive inhibition with an IC50 value about 6 times higher (87 µM) than the previously described for decavanadate (15 µM). We also found that both decavanadate and metformin-decavanadate exert antiproliferative effects on melanoma cells at 10 times lower concentrations than monomeric vanadate. Western blot analysis revealed that both, decavanadate and metformin-decavanadate increased phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine protein kinase AKT signaling proteins upon 24 h drug exposure, suggesting that the anti-proliferative activities of these compounds act independent of growth-factor signaling pathways.


Assuntos
Melanoma , Metformina , Adenosina Trifosfatases , Animais , Ânions , Humanos , Hipoglicemiantes , Melanoma/tratamento farmacológico , Metformina/farmacologia , Polieletrólitos , Coelhos , Vanadatos/farmacologia
4.
J Inorg Biochem ; 197: 110700, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31075720

RESUMO

Polyoxometalates (POMs) are promising inorganic inhibitors for P-type ATPases. The experimental models used to study the effects of POMs on these ATPases are usually in vitro models using vesicles from several membrane sources. Very recently, some polyoxotungstates, such as the Dawson anion [P2W18O62]6-, were shown to be potent P-type ATPase inhibitors; being active in vitro as well as in ex-vivo. In the present study we broaden the spectrum of highly active inhibitors of Na+/K+-ATPase from basal membrane of epithelial skin to the bi-capped Keggin-type anion phosphotetradecavanadate Cs5.6H3.4PV14O42 (PV14) and we confront the data with activity of other commonly encountered polyoxovanadates, decavanadate (V10) and monovanadate (V1). The X-ray crystal structure of PV14 was solved and contains two trans-bicapped α-Keggin anions HxPV14O42(9-x)-. The anion is built up from the classical Keggin structure [(PO4)@(V12O36)] capped by two [VO] units. PV14 (10 µM) exhibited higher ex-vivo inhibitory effect on Na+/K+-ATPase (78%) than was observed at the same concentrations of V10 (66%) or V1 (33%). Moreover, PV14 is also a potent in vitro inhibitor of the Ca2+-ATPase activity (IC50 5 µM) exhibiting stronger inhibition than the previously reported activities for V10 (15 µM) and V1 (80 µM). Putting it all together, when compared both P-typye ATPases it is suggested that PV14 exibited a high potential to act as an in vivo inhibitor of the Na+/K+-ATPase associated with chloride secretion.


Assuntos
ATPases Transportadoras de Cálcio/antagonistas & inibidores , Inibidores Enzimáticos , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Vanadatos , ATPases Transportadoras de Cálcio/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , ATPase Trocadora de Sódio-Potássio/metabolismo , Vanadatos/síntese química , Vanadatos/química , Vanadatos/farmacologia
5.
Metallomics ; 10(2): 287-295, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29313547

RESUMO

Polyoxometalates (POMs) are transition metal complexes that exhibit a broad diversity of structures and properties rendering them promising for biological purposes. POMs are able to inhibit a series of biologically important enzymes, including phosphatases, and thus are able to affect many biochemical processes. In the present study, we analyzed and compared the inhibitory effects of nine different polyoxotungstates (POTs) on two P-type ATPases, Ca2+-ATPase from skeletal muscle and Na+/K+-ATPase from basal membrane of skin epithelia. For Ca2+-ATPase inhibition, an in vitro study was performed and the strongest inhibitors were determined to be the large heteropolytungstate K9(C2H8N)5[H10Se2W29O103] (Se2W29) and the Dawson-type POT K6[α-P2W18O62] (P2W18) exhibiting IC50 values of 0.3 and 0.6 µM, respectively. Promising results were also shown for the Keggin-based POTs K6H2[CoW11TiO40] (CoW11Ti, IC50 = 4 µM) and Na10[α-SiW9O34] (SiW9, IC50 = 16 µM), K14[As2W19O67(H2O)] (As2W19, IC50 = 28 µM) and the lacunary Dawson K12[α-H2P2W12O48] (P2W12, IC50 = 11 µM), whereas low inhibitory potencies were observed for the isopolytungstate Na12[H4W22O74] (W22, IC50 = 68 µM) and the Anderson-type Na6[TeW6O24] (TeW6, IC50 = 200 µM). Regarding the inhibition of Na+/K+-ATPase activity, for the first time an ex vivo study was conducted using the opercular epithelium of killifish in order to investigate the effects of POTs on the epithelial chloride secretion. Interestingly, 1 µM of the most potent Ca2+-ATPase inhibitor, Se2W29, showed only a minor inhibitory effect (14% inhibition) on Na+/K+-ATPase activity, whereas almost total inhibition (99% inhibition) was achieved using P2W18. The remaining POTs exhibited similar inhibition rates on both ATPases. These results reveal the high potential of some POTs to act as P-type ATPase inhibitors, with Se2W29 showing high selectivity towards Ca2+-ATPase.


Assuntos
Fundulidae/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Compostos de Tungstênio/farmacologia , Animais , Fundulidae/crescimento & desenvolvimento , Conformação Proteica , Compostos de Tungstênio/química
6.
Dalton Trans ; 42(33): 11770-7, 2013 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-23636581

RESUMO

The putative applications of poly-, oligo- and mono-oxometalates in biochemistry, biology, pharmacology and medicine are rapidly attracting interest. In particular, these compounds may act as potent ion pump inhibitors and have the potential to play a role in the treatment of e.g. ulcers, cancer and ischemic heart disease. However, the mechanism of action is not completely understood in most cases, and even remains largely unknown in other cases. In the present review we discuss the most recent insights into the interaction between mono- and polyoxometalate ions with ion pumps, with particular focus on the interaction of decavanadate with Ca(2+)-ATPase. We also compare the proposed mode of action with those of established ion pump inhibitors which are currently in therapeutic use. Of the 18 classes of compounds which are known to act as ion pump inhibitors, the complete mechanism of inhibition is only known for a handful. It has, however, been established that most ion pump inhibitors bind mainly to the E2 ion pump conformation within the membrane domain from the extracellular side and block the cation release. Polyoxometalates such as decavanadate, in contrast, interact with Ca(2+)-ATPase near the nucleotide binding site domain or at a pocket involving several cytoplasmic domains, and therefore need to cross through the membrane bilayer. In contrast to monomeric vanadate, which only binds to the E2 conformation, decavanadate binds to all protein conformations, i.e. E1, E1P, E2 and E2P. Moreover, the specific interaction of decavanadate with sarcoplasmic reticulum Ca(2+)-ATPase has been shown to be non-competitive with respect to ATP and induces protein cysteine oxidation with concomitant vanadium reduction which might explain the high inhibitory capacity of V10 (IC50 = 15 µM) which is quite similar to the majority of the established therapeutic drugs.


Assuntos
Bombas de Íon/antagonistas & inibidores , Vanadatos/farmacologia , Relação Dose-Resposta a Droga , Bombas de Íon/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade , Vanadatos/química
7.
Dalton Trans ; 41(41): 12749-58, 2012 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-22968713

RESUMO

Recently we demonstrated that the decavanadate (V(10)) ion is a stronger Ca(2+)-ATPase inhibitor than other oxometalates, such as the isoelectronic and isostructural decaniobate ion, and the tungstate and molybdate monomer ions, and that it binds to this protein with a 1 : 1 stoichiometry. The V(10) interaction is not affected by any of the protein conformations that occur during the process of calcium translocation (i.e. E1, E1P, E2 and E2P) (Fraqueza et al., J. Inorg. Biochem., 2012). In the present study, we further explore this subject, and we can now show that the decaniobate ion, [Nb(10) = Nb(10)O(28)](6-), is a useful tool in deducing the interaction and the non-competitive Ca(2+)-ATPase inhibition by the decavanadate ion [V(10) = V(10)O(28)](6-). Moreover, decavanadate and vanadate induce protein cysteine oxidation whereas no effects were detected for the decaniobate, tungstate or molybdate ions. The presence of the antioxidant quercetin prevents cysteine oxidation, but not ATPase inhibition, by vanadate or decavanadate. Definitive V(IV) EPR spectra were observed for decavanadate in the presence of sarcoplasmic reticulum Ca(2+)-ATPase, indicating a vanadate reduction at some stage of the protein interaction. Raman spectroscopy clearly shows that the protein conformation changes that are induced by V(10), Nb(10) and vanadate are different from the ones induced by molybdate and tungstate monomer ions. Here, Mo and W cause changes similar to those by phosphate, yielding changes similar to the E1P protein conformation. The putative reduction of vanadium(V) to vanadium(IV) and the non-competitive binding of the V(10) and Nb(10) decametalates may explain the differences in the Raman spectra compared to those seen in the presence of molybdate or tungstate. Putting it all together, we suggest that the ability of V(10) to inhibit the Ca(2+)-ATPase may be at least in part due to the process of vanadate reduction and associated protein cysteine oxidation. These results contribute to the understanding and application of these families of mono- and polyoxometalates as effective modulators of many biological processes, particularly those associated with calcium homeostasis.


Assuntos
Antioxidantes/farmacologia , Cisteína/metabolismo , Inibidores Enzimáticos/farmacologia , Quercetina/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Vanádio/farmacologia , Animais , Quempferóis/farmacologia , Molibdênio/farmacologia , Nióbio/farmacologia , Oxirredução , Óxidos/farmacologia , Coelhos , Retículo Sarcoplasmático/enzimologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Compostos de Tungstênio/farmacologia , Vanadatos/farmacologia
8.
J Inorg Biochem ; 107(1): 82-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22178669

RESUMO

Over the last few decades there has been increasing interest in oxometalate and polyoxometalate applications to medicine and pharmacology. This interest arose, at least in part, due to the properties of these classes of compounds as anti-cancer, anti-diabetic agents, and also for treatment of neurodegenerative diseases, among others. However, our understanding of the mechanism of action would be improved if biological models could be used to clarify potential toxicological effects in main cellular processes. Sarcoplasmic reticulum (SR) vesicles, containing a large amount of Ca(2+)-ATPase, an enzyme that accumulates calcium by active transport using ATP, have been suggested as a useful model to study the effects of oxometalates on calcium homeostasis. In the present article, it is shown that decavanadate, decaniobate, vanadate, tungstate and molybdate, all inhibited SR Ca(2+)-ATPase, with the following IC(50) values: 15, 35, 50, 400 µM and 45 mM, respectively. Decaniobate (Nb(10)), is the strongest P-type enzyme inhibitor, after decavanadate (V(10)). Atomic-absorption spectroscopy (AAS) analysis, indicates that decavanadate binds to the protein with a 1:1 decavanadate:Ca(2+)-ATPase stoichiometry. Furthermore, V(10) binds with similar extension to all the protein conformations, which occur during calcium translocation by active transport, namely E1, E1P, E2 and E2P, as analysed by AAS. In contrast, it was confirmed that the binding of monomeric vanadate (H(2)VO(4)(2-); V(1)) to the calcium pump is favoured only for the E2 and E2P conformations of the ATPase, whereas no significant amount of vanadate is bound to the E1 and E1P conformations. Scatchard plot analysis, confirmed a 1:1 ratio for decavanadate-Ca(2+)-ATPase, with a dissociation constant, k(d) of 1 µM(-1). The interaction of decavanadate V(10)O(28)(6-) (V(10)) with Ca(2+)-ATPase is prevented by the isostructural and isoelectronic decaniobate Nb(10)O(28)(6-) (Nb(10)), whereas no significant effects were detected with ATP or with heparin, a known competitive ATP binding molecule, suggesting that V(10) binds non-competitively, with respect to ATP, to the protein. Finally, it was shown that decaniobate inhibits SR Ca(2+)-ATPase activity in a non competitive type of inhibition, with respect to ATP. Taken together, these data demonstrate that decameric niobate and vanadate species are stronger inhibitors of the SR calcium ATPase than simple monomeric vanadate, tungstate and molybdate oxometalates, thus affecting calcium homeostasis, cell signalling and cell bioenergetics, as well many other cellular processes. The ability of these oxometalates to act either as phosphate analogues, as a transition-state analogue in enzyme-catalysed phosphoryl group transfer processes and as potentially nucleotide-dependent enzymes modulators or inhibitors, suggests that different oxometalates may reveal different mechanistic preferences in these classes of enzymes.


Assuntos
ATPases Transportadoras de Cálcio/antagonistas & inibidores , Molibdênio/farmacologia , Nióbio/farmacologia , Óxidos/farmacologia , Retículo Sarcoplasmático/enzimologia , Compostos de Tungstênio/farmacologia , Vanadatos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Ligação Competitiva , ATPases Transportadoras de Cálcio/metabolismo , Heparina/farmacologia , Hidrólise , Ligação Proteica , Conformação Proteica , Coelhos , Retículo Sarcoplasmático/efeitos dos fármacos
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