Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche (CNR), Traversa La Crucca 3, 07100 Sassari, Italy.
Metallomics. 2019 Oct 16;11(10):1687-1699. doi: 10.1039/c9mt00174c.
Malignant melanoma (MM) is the most fatal skin cancer, whose incidence has critically increased in the last decades. Recent molecular therapies are giving excellent results in the remission of melanoma but often they induce drug resistance in patients limiting their therapeutic efficacy. The search for new compounds able to overcome drug resistance is therefore essential. Vanadium has recently been cited for its anticancer properties against several tumors, but only a few data regard its effect against MM. In a previous work we demonstrated the anticancer activity of four different vanadium species towards MM cell lines. The inorganic anion vanadate(v) (VN) and the oxidovanadium(iv) complex [VO(dhp)2] (VS2), where dhp is 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate, showed IC50 values of 4.7 and 2.6 μM, respectively, against the A375 MM cell line, causing apoptosis and cell cycle arrest. Here we demonstrate the involvement of Reactive Oxygen Species (ROS) production in the pro-apoptotic effect of these two V species and evaluate the activation of different cell cycle regulators, to investigate the molecular mechanisms involved in their antitumor activity. We establish that VN and VS2 treatments reduce the phosphorylation of extracellular-signal regulated kinase (ERK) by about 80%, causing the deactivation of the mitogen activated protein kinase (MAPK) pathway in A375 cells. VN and VS2 also induce dephosphorylation of the retinoblastoma protein (Rb) (VN 100% and VS2 90%), together with a pronounced increase of cyclin-dependent kinase inhibitor 1 p21 (p21Cip1) protein expression up to 1800%. Taken together, our results confirm the antitumor properties of vanadium against melanoma cells, highlighting its ability to induce apoptosis through generation of ROS and cell cycle arrest by counteracting MAPK pathway activation and strongly inducing p21Cip1 expression and Rb hypo-phosphorylation.
恶性黑色素瘤（MM）是最致命的皮肤癌，在过去几十年中其发病率急剧上升。最近的分子疗法在缓解黑色素瘤方面取得了极好的效果，但它们经常在患者中诱导耐药性，从而限制了其治疗效果。因此，寻找能够克服耐药性的新化合物是至关重要的。钒最近因其对几种肿瘤的抗癌特性而被引用，但只有少数数据涉及它对 MM 的影响。在之前的工作中，我们证明了四种不同的钒物种对 MM 细胞系的抗癌活性。无机阴离子钒酸盐（VN）和氧化钒（IV）配合物[VO（dhp）2]（VS2），其中 dhp 是 1,2-二甲基-3-羟基-4（1H）-吡啶酮，对 A375 MM 细胞系的 IC50 值分别为 4.7 和 2.6 μM，导致细胞凋亡和细胞周期停滞。在这里，我们证明了活性氧（ROS）的产生参与了这两种 V 物种的促凋亡作用，并评估了不同细胞周期调节剂的激活情况，以研究其抗肿瘤活性的分子机制。我们确定 VN 和 VS2 处理使 A375 细胞中的细胞外信号调节激酶（ERK）磷酸化减少约 80%，从而使丝裂原激活蛋白激酶（MAPK）途径失活。VN 和 VS2 还诱导视网膜母细胞瘤蛋白（Rb）的去磷酸化（VN 为 100%，VS2 为 90%），同时细胞周期蛋白依赖性激酶抑制剂 1 p21（p21Cip1）蛋白表达显著增加至 1800%。综上所述，我们的结果证实了钒对黑色素瘤细胞的抗肿瘤特性，强调了其通过生成 ROS 诱导细胞凋亡和通过抑制 MAPK 途径激活和强烈诱导 p21Cip1 表达和 Rb 低磷酸化来诱导细胞周期停滞的能力。
