Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 13, Issue 9B, Pages 3960-3972Publisher
WILEY
DOI: 10.1111/j.1582-4934.2009.00708.x
Keywords
melanoma; sodium pump; cMyc; cardenolides; brain metastasis; chemoresistance
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Funding
- Fonds Yvonne Boel (Brussels, Belgium)
- Region de Bruxelles-Capitale (Brussels, Belgium)
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Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump alpha sub-units has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump alpha 1 activity by means of selective ligands, that are cardiotonic steroids, markedly impairs cell migration and kills apoptosis-resistant cancer cells. The objective of this study was to determine the expression levels of sodium pump alpha sub-units in melanoma clinical samples and cell lines and also to characterize the role of alpha 1 sub-units in melanoma cell biology. Quantitative RT-PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump alpha sub-units. In vitro cytotoxicity of various cardenolides and of an anti-alpha 1 siRNA was 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. Our data show that all investigated human melanoma cell lines expressed high levels of the alpha 1 sub-unit, and 33% of human melanomas displayed significant alpha 1 sub-unit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti-tumour 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-tumour activity in the aggressive human metastatic brain melanoma model in vivo. The alpha 1 sodium pump sub-unit could represent a potential novel target for combating melanoma.
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