No abstract

Narciclasine (1) is a plant growth regulator that has been previously demonstrated to be proapoptotic to cancer cells at high concentrations (> or = 1 microM). Data generated in the present study show that narciclasine displays potent antitumor effects in apoptosis-resistant as well as in apoptosis-sensitive cancer cells by impairing the organization of the actin cytoskeleton in cancer cells at concentrations that are not cytotoxic (IC(50) values of 30-90 nM). The current study further revealed that any chemical modification to the narciclasine backbone generally led to compounds of variable stability, weaker activity, or even the complete loss of antiproliferative effects in vitro. However, one hemisynthetic derivative of narciclasine, compound 7k, demonstrated by both the intravenous and oral routes higher in vivo antitumor activity in human orthotopic glioma models in mice when compared to narciclasine at nontoxic doses. Narciclasine and compound 7k may therefore be of potential use to combat brain tumors.

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 alpha1 subunit as a novel target in NSCLC and revealed that alpha1 expression is markedly higher in a significant proportion of NSCLC clinical samples compared to normal lung tissue. Furthermore, reduction in alpha1 expression in A549 NSCLC cells by anti-alpha1 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 (alpha1beta1, alpha2beta1 and alpha3beta1), most strikingly of alpha1beta1. 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 alpha1. The marked impairment in A549 NSCLC cell proliferation and migration, and resulting similar morphology following anti-alpha1 siRNA 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 alpha1 using specific cardenolides could represent a novel means to combat certain NSCLCs.

Analysis of the methanolic extract of Calotropis procera root barks enabled the identification of a novel cardenolide (2''-oxovoruscharin) to be made. Of the 27 compounds that we hemisynthesized, one (23) exhibited a very interesting profile with respect to its hemisynthetic chemical yield, its in vitro antitumor activity, its in vitro inhibitory influence on the Na+/K+-ATPase activity, and its in vivo tolerance. Compound 23 displayed in vitro antitumor activity on a panel of 57 human cancer cell lines similar to taxol, and higher than SN-38 (the active metabolite of irinotecan), two of the most potent drugs used in hospitals to combat cancer.