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Synergistic antiproliferative effect of valproic acid and 5,7-dimethoxycoumarin against A2058 human melanoma cells

Ewa Chodurek ,  Daniel Wolny ,  Zofia Dzierżewicz 

Department of Biopharmacy, Medical University of Silesia, Jedności 8, Sosnowiec 41-200, Poland


Melanoma is one of the most malignant tumours of a dangerous high incidence and high metastatic potential. It grows quickly and in an advanced stage is resistant to radio-, chemo- and immunotherapy, which makes it difficult to cure. Therefore, research efforts are focused on the development of new therapeutics or chemopreventive strategies [1]. One of the histone deacetylase inhibitors - valproic acid (VPA) – appears to be very promising new anticancer agent with pro-apoptotic, antiproliferative, and differentiation-stimulating properties. The natural compound, 5,7-dimethoxycoumarin (DMC), also has chemopreventive potential due to its pro-differentiation activity. Probably the differentiation activity of these compounds is associated with activation of the neoplastic cell differentiation inducing genes and the interference with the mitogen-activated protein kinase signalling pathway [2, 3].

The aim of the study was to investigate whether the VPA and DMC has a synergistic antiproliferative activity against A2058 human melanoma cell line.

A2058 cells were cultured on Minimal Essential Medium in standard conditions. Cells were cultured in 96-well plates (initial density 103 cells/well) for 24 h. Subsequently, the cells were treated with VPA (concentration range: 0.1–10 mM), DMC (10–500 μM), and a combination of 1 mM VPA with 10, 50, 100 or 150 μM DMC. The effect of VPA and DMC on the cell proliferation was measured using the sulforhodamine B based In Vitro Toxicology Assay Kit (Sigma–Aldrich) after 72 hours of incubation.

Pronounced antiproliferative effect was observed when using 1 mM of VPA or 50 μM of DMC. Slightly synergistic effect was observed in the case of combined use of 1 mM VPA and lower concentrations of DMC (10 and 50 μM).


[1] L. Sigalotti, A. Covre, E. Fratta, G. Parisi, F. Colizzi, A. Rizzo, R. Danielli, H.J. Nico-lay, S. Coral, M. Maio, Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies, Journal of Translational Medicine 8 (2010)56.

[2] K. Gotfryd, G. Skladchikova, E.A. Lepekhin, V. Berezin, E. Bock, P.S. Walmod,Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation, BMC Cancer 10 (2010) 383

[3] D. Alesiani, R. Cicconi, M. Mattei, R. Bei, A. Canini, Inhibition of Mek 1/2kinase activity and stimulation of melanogenesis by 5,7-dimethoxycoumarintreatment of melanoma cells, International Journal of Oncology 34 (6) (2009)1727–1735.


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Submitted: 2014-03-12 13:19
Revised:   2014-05-02 19:39