Background. 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 MM but most of them develops an acquired drug resistance, limiting the therapeutic efficacy. The search for new compounds able to overcome drug resistance is therefore essential. Vanadium is a trace element present in the diet and essential in small quantities for normal metabolism and growth of mammals. Antitumor effects of vanadium compounds are described against several tumors, but only few data are reported regarding vanadium effect against MM. On this regard we selected four different vanadium compounds: the inorganic anion vanadate(V) (indicated with VN), and three oxidovanadium(IV) complexes, [VIVO(dhp)2] where dhp- is the anion 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS2), [VIVO(mpp)2] where mpp- is 1-methyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS3), and [VIVO(ppp)2] where ppp- is 1-phenyl-2-methyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS4). The antitumor effects of these compounds were studied against two different MM cell lines (A375 and CN-mel) and a fibroblast cell line (BJ) as normal control. Material and Methods. Antiproliferative assays, using the vanadium compounds in crescent doses and times of exposure, allowed us to calculate the IC50 values of the four selected compounds for each cell line, highlighting their antitumor potentiality. In order to investigate the molecular mechanisms underlining such an antiproliferative effect we carried out apoptosis and cell cycle analyses using the Tali® cytometer, to detect phosphatidylserine exposure and cell cycle phases modifications following treatments. Results. All tested compounds exert antiproliferative activity on MM cells in a dose dependent manner. After 72 hours of treatment, we calculated IC50 values starting from 2.4 ?M up to 14 ?M depending on the cell line analyzed and compound tested. Ligands of each vanadium coordination complex VS2, VS3 and VS4 were analyzed separately in order to assess their possible cytotoxicity. PPP ligand turned to be toxic for MM cells and VS4 was then excluded from the following analyses. The A375 MM cell line appeared to be the most sensitive cell line, being inhibited by ?M concentrations of all the compounds. VN and VS2 were the two most active compounds (IC50 of 4.7 and 2.6 ?M, respectively). We then evaluated the pro-apoptotic activity and the ability to interfere with the cell cycle progression of VS2 and VN on the A375 cell line. Our results showed that both VS2 and VN were able to induce apoptosis in a dose and time dependent manner. Conversely, the cell cycle arrest occurred at different phases for the two V species analyzed (G2 checkpoint for VN and G0/G1 for VS2), showing the importance of the chemical form in determining their mechanism of action. Conclusions. Our results confirm the antitumor properties of vanadium against melanoma cells highlighting its ability to inhibit in vitro tumor growth and to induce apoptosis and cell cycle arrest. These results throw the basis for a future work in which these properties can be investigated in more detail at the molecular level.

Antitumoral effects of Vanadium compounds in malignant melanoma cell lines

Marina Pisano;Maria Serra;Giuseppe Palmieri;Daniele Sanna;Eugenio Garribba;Carla Rozzo
2017

Abstract

Background. 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 MM but most of them develops an acquired drug resistance, limiting the therapeutic efficacy. The search for new compounds able to overcome drug resistance is therefore essential. Vanadium is a trace element present in the diet and essential in small quantities for normal metabolism and growth of mammals. Antitumor effects of vanadium compounds are described against several tumors, but only few data are reported regarding vanadium effect against MM. On this regard we selected four different vanadium compounds: the inorganic anion vanadate(V) (indicated with VN), and three oxidovanadium(IV) complexes, [VIVO(dhp)2] where dhp- is the anion 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS2), [VIVO(mpp)2] where mpp- is 1-methyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS3), and [VIVO(ppp)2] where ppp- is 1-phenyl-2-methyl-3-hydroxy-4(1H)-pyridinonate (indicated with VS4). The antitumor effects of these compounds were studied against two different MM cell lines (A375 and CN-mel) and a fibroblast cell line (BJ) as normal control. Material and Methods. Antiproliferative assays, using the vanadium compounds in crescent doses and times of exposure, allowed us to calculate the IC50 values of the four selected compounds for each cell line, highlighting their antitumor potentiality. In order to investigate the molecular mechanisms underlining such an antiproliferative effect we carried out apoptosis and cell cycle analyses using the Tali® cytometer, to detect phosphatidylserine exposure and cell cycle phases modifications following treatments. Results. All tested compounds exert antiproliferative activity on MM cells in a dose dependent manner. After 72 hours of treatment, we calculated IC50 values starting from 2.4 ?M up to 14 ?M depending on the cell line analyzed and compound tested. Ligands of each vanadium coordination complex VS2, VS3 and VS4 were analyzed separately in order to assess their possible cytotoxicity. PPP ligand turned to be toxic for MM cells and VS4 was then excluded from the following analyses. The A375 MM cell line appeared to be the most sensitive cell line, being inhibited by ?M concentrations of all the compounds. VN and VS2 were the two most active compounds (IC50 of 4.7 and 2.6 ?M, respectively). We then evaluated the pro-apoptotic activity and the ability to interfere with the cell cycle progression of VS2 and VN on the A375 cell line. Our results showed that both VS2 and VN were able to induce apoptosis in a dose and time dependent manner. Conversely, the cell cycle arrest occurred at different phases for the two V species analyzed (G2 checkpoint for VN and G0/G1 for VS2), showing the importance of the chemical form in determining their mechanism of action. Conclusions. Our results confirm the antitumor properties of vanadium against melanoma cells highlighting its ability to inhibit in vitro tumor growth and to induce apoptosis and cell cycle arrest. These results throw the basis for a future work in which these properties can be investigated in more detail at the molecular level.
2017
Istituto di Chimica Biomolecolare - ICB - Sede Pozzuoli
malignant melanoma
vanadium compounds
apoptosis
cell cycle
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/328750
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