ANTIPROLIFERATIVE ACTIVITY OF VANADIUM COMPOUNDS: EFFECTS ON THE MAJOR MALIGNANT MELANOMA MOLECULAR PATHWAYS

Malignant melanoma (MM) is the most fatal skin cancer whose incidence is critically increasing in the last decades. Recent molecular therapies are giving excellent results in the remission of melanoma but often they induce drug resistance in the 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 few data regard its effect against MM. In a previous work we demonstrated the anticancer activity of four different vanadium species on MM cell lines. The inorganic anion vanadate(V) (VN) and the oxidovanadium(IV) complex [VO(dhp)2], where dhp is 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate, (VS2) showed IC50 values of 4.7 and 2.6 ?M respectively, against 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) of about 80%, causing the deactivation of mitogen activated protein kinases (MAPK) pathway in A375 cells. VN and VS2 also induce dephosphorylation of 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 contrasting MAPK pathway activation and strongly inducing p21Cip1 expression and Rb hypo-phosphorylation.