The saponin digitonin, the aglycone digitoxigenin and five cardiac glycosides were evaluated for cytotoxicity using primary cultures of tumor cells from patients and a human cell line panel (representing different cytotoxic drug-resistance patterns). Of these seven compounds, proscillaridin A was the most potent (IC50: 6.4-76 nM), followed by digitoxin, and then ouabain, digoxin, lanatoside C, digitoxigenin and digitonin. Correlation analysis of the log IC50 values for the cell lines in the panel showed that compound cytotoxicity was only slightly influenced by resistance mechanisms that involved P-glycoprotein, topoisomerase II, multidrug resistance-associated protein and glutathione-mediated drug resistance. Digitoxin and digoxin expressed selective toxicity against solid tumor cells from patients, while proscillaridin A expressed no selective toxicity against either solid or hematological tumor cells. The results revealed marked differences in cytotoxicity between the cardiac glycosides, both in potency and selectivity, and modes of action for cytotoxicity that differ from that of commonly used anticancer drugs.
1Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, PO Box 574, 751 23 Uppsala, Sweden. 2Division of Clinical Pharmacology, University Hospital, Uppsala University, 751 85 Uppsala, Sweden.
This work was supported by grants from the Swedish Cancer Foundation.
Correspondence to P Claeson, Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, PO Box 574, 751 23 Uppsala, Sweden. Tel: (+46) 18 4714479; Fax: (+46) 18 509101; e-mail: firstname.lastname@example.org
(Received 13 February 2001; accepted 10 March 2001)