Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Faro, Portugal; Algarve Biomedical Center (ABC), Faro, Portugal; Escola Superior de Saúde (ESS), Universidade do Algarve, Faro, Portugal.
Faculdade de Ciências e Tecnologia (FCT), Universidade do Algarve, Faro, Portugal; Centro de Ciências do Mar (CCMar), Universidade do Algarve, Faro, Portugal.
J Inorg Biochem. 2022 Oct;235:111915. doi: 10.1016/j.jinorgbio.2022.111915. Epub 2022 Jul 8.
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 Ca-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 Ca-ATPase by a mixed-type competitive-non-competitive inhibition with an IC 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.
多钒酸盐是一种多金属氧酸盐（POMs），具有广泛的生物活性，包括抗糖尿病和抗癌活性。重要的是，基于钒的化合物以及抗糖尿病双胍类药物，如二甲双胍，已被证明对黑色素瘤具有治疗作用。这些药物的联合用药，即二甲双胍-多钒酸盐复合物，也因其抗糖尿病作用而得到认可，最近被描述为比二甲双胍单药治疗更好的治疗方法，使糖尿病啮齿动物模型中的剂量降低。在此，我们比较了多钒酸盐和二甲双胍-多钒酸盐对兔骨骼肌肌浆网囊泡中 Ca-ATP 酶活性的影响，以及对人黑色素瘤细胞中细胞信号事件和活力的影响。我们表明，与多钒酸盐介导的非竞争性机制不同，二甲双胍-多钒酸盐通过混合竞争-非竞争抑制抑制 Ca-ATP 酶，IC 值约高 6 倍（87 μM），而不是先前描述的多钒酸盐（15 μM）。我们还发现，多钒酸盐和二甲双胍-多钒酸盐在 10 倍于单体钒酸盐的低浓度下对黑色素瘤细胞均具有抗增殖作用。Western blot 分析表明，多钒酸盐和二甲双胍-多钒酸盐在药物暴露 24 小时后均增加细胞外信号调节激酶（ERK）和丝氨酸/苏氨酸蛋白激酶 AKT 信号蛋白的磷酸化，表明这些化合物的抗增殖活性独立于生长因子信号通路。
