Abstract
In the past decade, there has been a profound increase in the number of studies revealing that cardenolide glycosides display inhibitory activity on the growth of human cancer cells. The use of potential cardenolide glycosides may be a worthwhile approach in anticancer research. Reevesioside A, a cardenolide glycoside isolated from the root of Reevesia formosana, displayed potent anti-proliferative activity against human hormone-refractory prostate cancers. A good correlation (r2 = 0.98) between the expression of Na+/K+-ATPase α3 subunit and anti-proliferative activity suggested the critical role of the α3 subunit. Reevesioside A induced G1 arrest of the cell cycle and subsequent apoptosis in a thymidine block-mediated synchronization model. The data were supported by the down-regulation of several related cell cycle regulators, including cyclin D1, cyclin E and CDC25A. Reevesioside A also caused a profound decrease of RB phosphorylation, leading to an increased association between RB and E2F1 and the subsequent suppression of E2F1 activity. The protein and mRNA levels of c-myc, which can activate expression of many downstream cell cycle regulators, were dramatically inhibited by reevesioside A. Transient transfection of c-myc inhibited the down-regulation of both cyclin D1 and cyclin E protein expression to reevesioside A action, suggesting that c-myc functioned as an upstream regulator. Flow cytometric analysis of JC-1 staining demonstrated that reevesioside A also induced the significant loss of mitochondrial membrane potential. In summary, the data suggest that reevesioside A inhibits c-myc expression and down-regulates the expression of CDC25A, cyclin D1 and cyclin E, leading to a profound decrease of RB phosphorylation. G1 arrest is, therefore, induced through E2F1 suppression. Consequently, reevesioside A causes mitochondrial damage and an ultimate apoptosis in human hormone-refractory prostate cancer cells.
Highlights
Cardenolide glycosides, a class of steroid-like compounds, are well appreciated in the treatment of congestive heart failure and arrhythmia
It has been documented recently that the anticancer activities induced by cardenolide glycosides occurred at concentrations that are achievable in humans without toxic effects
The determination of the anticancer activity against prostate cancers in the present study showed that reevesioside A displayed potent activity in blocking c-myc expression and inducing arrest of the cell cycle as well as cell apoptosis
Summary
Cardenolide glycosides, a class of steroid-like compounds, are well appreciated in the treatment of congestive heart failure and arrhythmia. The mechanism of action arises from the inhibition of Na+/K+-ATPase, leading to an increase of intracellular Ca2+ concentrations [1]. It has been documented recently that the anticancer activities induced by cardenolide glycosides occurred at concentrations that are achievable in humans without toxic effects. It has been suggested that this class of compounds may be useful for anticancer treatment [1,2,3]. A variety of studies have identified the anti-proliferative effects of cardenolide glycosides in human malignant tumor cells. The diverse mechanisms have been reported to be involved in the exposure to this class of compounds, including the increase of intracellular
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