Résumé : Abstract Background: Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump alpha subunits has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump alpha1 activity by means of selective ligands i.e. cardenolides, markedly impairs cell migration and kills apoptosis-resistant cancer cells. Objectives: To determine the expression levels of sodium pump alpha subunits in melanoma clinical samples and cell lines, and to characterize the role of alpha1 subunits in melanoma cell biology. Methods: Quantitative RT-PCR, western blotting and immunohistochemistry were used to determine the expression levels of sodium pump alpha subunits. In vitro cytotoxicity of various cardenolides and of an anti-alpha1 siRNA were evaluated by means of MTT assay, quantitative videomicroscopy and through apoptosis assays. The in vivo activity of a novel cardenolide UNBS1450 was evaluated in a melanoma brain metastasis model. Results: Our data show that all investigated human melanoma cell lines expressed high levels of the alpha1 subunit and 33% of human melanomas displayed significant alpha1 subunit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti-tumor effects against melanomas in vitro. This activity was closely paralleled by decreases in cMyc expression and by increases in apoptotic features. UNBS1450 also displayed marked anti-tumor activity in the aggressive human metastatic brain melanoma model in vivo. Conclusion: The alpha1 sodium pump subunit could represent a potential novel target for combating melanoma.