The α1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers

With an overall 5 year survival rate as low as 15% for non-small cell lung cancer (NSCLC), even with surgical intervention and the use of newer molecules in adjuvant chemotherapy, there is an urgent need for new biological targets and associated novel anti-cancer agents. The present study was undertaken to evaluate the potential of the Na+/K+-ATPase al subunit as a novel target in NSCLC and revealed that al expression is markedly higher in a significant proportion of NSCLC clinical samples compared to normal lung tissue. Furthermore, reduction in al expression in A549 NSCLC cells by anti-alpha 1 siRNA resulted in markedly impaired proliferation and migration of these cancer cells. Finally, of three cardenolides investigated, UNBS1450, which is known to bind to Na+/K+-ATPase and displays potent anti-tumour activity in vivo in experimental models of human NSCLCs, is the most potent inhibitor of Na+/K+-ATPase isozymes (alpha 1 beta 1, alpha 2 beta 1 and alpha 3 beta 1), most strikingly of alpha 1 beta 1. This was reflected in the compound's more potent anti-proliferative activity in all NSCLC cell lines evaluated (A549, Cal-12T, NCI-H727 and A427); the first three of which over-express al. The marked impairment in A549 NSCLC cell proliferation and migration, and resulting similar morphology following anti-alpha 1 ARNA or UNBS1450 treatment, was associated with features of abnormal cytokinesis, mediated in the case of UNBS1450 by disorganization of the actin cytoskeleton. Collectively these data strongly suggest that targeting the Na+/K+-ATPase oil using specific cardenolides could represent a novel means to combat certain NSCLCs. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.