Pro-apoptotic and cytostatic activity of naturally occurring cardenolides

Abstract

Cardenoliddes are steroid glycosides which are known to exert cardiotonic effects by inhibiting the Na+/K+-ATPase. Several of these compds. have been shown also to possess anti-tumor potential. The aim of the present work was the characterization of the tumor cell growth inhibition activity of four cardenolides, isolated from Periploca graeca L., and the mechanisms underlying such an effect. The pro-apoptotic and cytostatic effect of the compds. was tested in U937 (monocytic leukemia) and PC3 (prostate adenocarcinoma). Characterization of apoptosis and cell cycle impairment was obtained by cytofluorimetry and WB. Periplocymarin and periplocin were the most active compds., periplocymarin being more effective than the ref. compd. ouabain. The redn. of cell no. by these two cardenolides was due in PC3 cells mainly to the activation of caspase-dependent apoptotic pathways, while in U937 cells to the induction of cell cycle impairment without extensive cell death. Interestingly, periplocymarin, at cytostatic but non-cytotoxic doses, was shown to sensitize U937 cells to TRAIL. Taken together, our data outline that cardiac glycosides are promising anticancer drugs and contribute to the identification of new natural cardiac glycosides to obtain chem. modified non-cardioactive/low toxic derivs. with enhanced anticancer potency