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