digitoxin and Colonic-Neoplasms

Colon ischemia (CI) is the most common form of ischemic injury of the gastrointestinal tract. Determining the precise incidence of CI is a challenging task, because of its often brief, mild nature, and frequent spontaneous resolution, as well as its misdiagnosis as other diseases. While many underlying disease conditions may predispose patients to CI, an important and possibly overlooked etiology is that of pharmacologically induced alterations of colonic blood flow. This review details the pharmacologic agents known to be associated with CI; when possible, their mechanisms of action are described. The aim of this paper is to highlight this often unrecognized cause of CI, thereby helping physicians to be aware of the association, to recognize its occurrence promptly, and to possibly reduce morbidity and mortality.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Appetite Depressants; Colon; Colonic Neoplasms; Constipation; Digitalis; Humans; Ischemia; Nasal Decongestants

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.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cardenolides; Colonic Neoplasms; Digitoxin; Digoxin; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Irinotecan; NF-kappa B; Proscillaridin; Strophanthins