title: Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs.
abstract: Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited somewhat lower activity (IC50 values 0.27-4.1 microM). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.
authors.affiliation: Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Center, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden. jenny.felth@fkog.uu.se
authors.forename: Jenny
authors.initials: J
authors.lastname: Felth
authors.forename: Linda
authors.initials: L
authors.lastname: Rickardson
authors.forename: Josefin
authors.initials: J
authors.lastname: Rosén
authors.forename: Malin
authors.initials: M
authors.lastname: Wickström
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.forename: Magnus
authors.initials: M
authors.lastname: Lindskog
authors.forename: Lars
authors.initials: L
authors.lastname: Bohlin
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002298:Cardenolides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy; D004074:Digitoxin / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D004077:Digoxin / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D016328:NF-kappa B / Q000187:drug effects; D011442:Proscillaridin / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D013328:Strophanthins / Q000097:blood / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002298:Cardenolides; D016328:NF-kappa B; D013328:Strophanthins; D004077:Digoxin; D000077146:Irinotecan; D004074:Digitoxin; C021065:oleandrin; C000505:convallatoxin; D011442:Proscillaridin; D002166:Camptothecin