Abstract
Cardiac glycosides such as oleandrin are known to inhibit the Na,K-ATPase pump, resulting in a consequent increase in calcium influx in heart muscle. Here, we investigated the effect of oleandrin on the growth of human and mouse cancer cells in relation to Na,K-ATPase subunits. Oleandrin treatment resulted in selective inhibition of human cancer cell growth but not rodent cell proliferation, which corresponded to the relative level of Na,K-ATPase alpha3 subunit protein expression. Human pancreatic cancer cell lines were found to differentially express varying levels of alpha3 protein, but rodent cancer cells lacked discernable expression of this Na,K-ATPase isoform. A correlation was observed between the ratio of alpha3 to alpha1 isoforms and the level of oleandrin uptake during inhibition of cell growth and initiation of cell death; the higher the alpha3 expression relative to alpha1 expression, the more sensitive the cell was to treatment with oleandrin. Inhibition of proliferation of Panc-1 cells by oleandrin was significantly reduced when the relative expression of alpha3 was decreased by knocking down the expression of alpha3 isoform with alpha3 siRNA or increasing expression of the alpha1 isoform through transient transfection of alpha1 cDNA to the cells. Our data suggest that the relative lack of alpha3 (relative to alpha1) in rodent and some human tumor cells may explain their unresponsiveness to cardiac glycosides. In conclusion, the relatively higher expression of alpha3 with the limited expression of alpha1 may help predict which human tumors are likely to be responsive to treatment with potent lipid-soluble cardiac glycosides such as oleandrin.
Highlights
Cardiac glycosides are a class of compounds used to treat congestive heart failure by increasing myocardial contractile force [1]
Oleandrin is a cardiac glycoside derived from Nerium oleander, which has been used for many years in Russia and China for this purpose
We hypothesized that the relative expression of Na,K-ATPase subunits led to a differential cellular response to treatment with cardiac glycosides
Summary
Cardiac glycosides are a class of compounds used to treat congestive heart failure by increasing myocardial contractile force [1]. In contrast to its use for the treatment of heart failure, preclinical and retrospective patient data suggest that cardiac glycosides (e.g., digoxin, digitoxin, ouabain, and oleandrin), may reduce the growth of various cancers including breast, lung, prostate, and leukemia [2,3,4,5,6,7]. Other investigators have reported that cardiac glycoside drugs, such as digitoxin and oleandrin, inhibit the constitutive hypersecretion of nuclear factor κB–dependent proinflammatory cytokine interleukin 8 from cystic fibrosis lung epithelial cells [13]. These investigators observed that oleandrin, as well as digoxin, suppressed the tumor necrosis factor-α/nuclear factor κB signaling pathway by blocking tumor necrosis factorα–dependent TNFR1/TRADD complex formation [14]. We sought to better understand the mechanisms that might be responsible for the selective anticancer activity of this potent cardiac glycoside and the compounds related to it
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