期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 235, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2022.111915
关键词
Decavanadate; Metformin; Metformin-decavanadate; Polyoxometalates; Polyoxovanadates; Skin cancer; Melanoma; Cell signaling
资金
- Spanish Ministry of Science, Innovation and Universities [RTI2018-094629-B-I00]
- Funda?a?o para a Cie?ncia e a Tecnologia (FCT) [PTDC/MED-ONC/4167/2020 ?]
- Fundação para a Ciência e a Tecnologia [PTDC/MED-ONC/4167/2020] Funding Source: FCT
The metformin-decavanadate complex inhibits Ca2+-ATPase through a mixed-type competitive-non-competitive inhibition, with a higher IC50 value compared to decavanadate. Both decavanadate and metformin-decavanadate exhibit antiproliferative effects on melanoma cells at lower concentrations than monomeric vanadate. The compounds also increase phosphorylation of ERK and AKT signaling proteins, suggesting the anti-proliferative activities are independent of growth-factor signaling pathways.
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 mu M) than the previously described for decavanadate (15 mu M). 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.
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