Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials

• Published in: Investigational new drugs Vol. 31; no. 4; pp. 1087 - 1094
• Main Authors: Slingerland, M., Cerella, C., Guchelaar, H. J., Diederich, M., Gelderblom, H.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.08.2013; Springer; Springer Nature B.V
• Subjects: Acidification; Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Cancer therapies; Cardiac Glycosides - chemistry; Cardiac Glycosides - pharmacology; Cardiac Glycosides - therapeutic use; Cardiovascular disease; Cell death; Cell Death - drug effects; Clinical trials; Clinical Trials as Topic; Cytotoxicity; Drug dosages; Drug Screening Assays, Antitumor; Drug therapy; Drugs; General aspects; Homeostasis; Humans; Kinases; Medical sciences; Medicine; Medicine & Public Health; Neoplasms - drug therapy; Oncology; Pharmaceutical sciences; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Review; Studies; Cardenolide; Na; Cell death; ATPase; Cardiac glycoside; Cytotoxicity; UNBS1450; K; Antineoplastic agent; Cardiotonic agent; Enzyme; Preclinical trial; Cardiovascular disease; Heart disease; Phase I trial; UNBS 1450; Hydrolases; exchanging ATPase; Glycoside; Mechanism of action; Apoptosis
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-013-9984-1

Summary Cardiac glycosides have a long history in the treatment of cardiac disease. However, several preclinical studies as well as two phase I studies have shown that cardenolides may also possess anticancer effects. The mechanisms of these anticancer effects may include intracellular decrease of K + and increase of Na + and Ca 2+ ; intracellular acidification; inhibition of IL-8 production and of the TNF-α/NF-κB pathway; inhibition of DNA topoisomerase II and activation of the Src kinase pathway. To date three cardiac glycosides have been developed for treatment of cancer and were tested in a phase 1 clinical trial to determine dose limiting toxicities and maximum tolerated dose. Future studies of this novel class of anticancer drugs are warranted to determine their possible role in cancer treatment.