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Melanoma is one of the most dangerous skin malignancies due to its highmetastatic tendency and high mortality. Activation of key signaling pathwaysenforcing melanoma progression depends on phosphorylation of tyrosine kinases,and oxidative stress. We here investigated the effect of the new bis-coumarinderivative (3,5-DCPBC) on human melanoma cell survival, growth, proliferation,migration, and intracellular redox state, and deciphered associated signalpathways. This novel derivative was found to be toxic for melanoma cells, andnon-toxic for their benign counterparts, melanocytes and fibroblasts. 3,5-DCPBCinhibited cell survival, migration and proliferation of different metastatic,and non-metastatic melanoma cell lines through the profound suppression ofphosphorylation of the Epidermal Growth Factor receptor, and related downstreampathways. Suppression of phosphorylation of key downstream transcriptionfactors and different tyrosine kinases comprise JAK/STAT, SRC kinases, ERK andMAP kinases (p38alpha), all involved in melanoma progression. Simultaneous andspecific targeting of multiple tyrosine kinases and corresponding key genes inmelanoma cells makes 3,5-DCPBC a highly interesting anti-melanoma, andanti-metastatic drug candidate which may in the long term hold promise in thetherapy of advanced melanoma.

A Novel Bis-Coumarin Targets Multiple Tyrosine Kinases of Key Signaling  Pathways in Melanoma and Inhibits Melanoma Cell Survival, Proliferation, and  Migration