Pro-apoptotic and cytostatic activity of naturally occurring cardenolides.
OBJECTIVE
Cardenoliddes are steroid glycosides which are known to exert cardiotonic effects by inhibiting the Na(+)/K(+)-ATPase. Several of these compounds 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.


METHODS
The pro-apoptotic and cytostatic effect of the compounds was tested in U937 (monocytic leukemia) and PC3 (prostate adenocarcinoma). Characterization of apoptosis and cell cycle impairment was obtained by cytofluorimetry and WB.


RESULTS
Periplocymarin and periplocin were the most active compounds, periplocymarin being more effective than the reference compound ouabain. The reduction of cell number 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.


CONCLUSIONS
Taken together, our data outline that cardiac glycosides are promising anticancer drugs and contribute to the identification of new natural cardiac glycosides to obtain chemically modified non-cardioactive/low toxic derivatives with enhanced anticancer potency.
Bloise
Elena
E
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, Fisciano, SA, Italy.
Braca
Alessandra
A
De Tommasi
Nunziatina
N
Belisario
Maria Antonietta
MA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002298:Cardenolides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D002298:Cardenolides; D017931:DNA Primers; D004791:Enzyme Inhibitors; D000254:Sodium-Potassium-Exchanging ATPase