Cardiac glycosides constitute a diverse family of naturally derived compounds widely known for their ability to bind to, and inhibit, the sodium pump. Members of this family of compounds have been at the clinic for many years, for the treatment of heart failure and atrial arrhythmia. The mechanism of their positive inotropic effect is one of the best described, among all known drugs. However, exciting recent findings suggest additional signaling modes of action of the sodium pump, implicating cardiac glycosides in the regulation of several important cellular processes and highlight their potential new therapeutic roles. Our initial in vitro experiments verify the increased susceptibility of cancer cells to these compounds. Even though the first generation of glycoside-based anticancer drugs is currently in clinical trials, much less are known for their underlying molecular mechanism. We conducted a high throughput screening study and found cardiac glycosides to be potent inhibitors of tissue kallikrein expression. Furthermore we showed that this effect could be attributed to a dramatic downregulation of c-myc transcription factor. At the same time, emerging literature adds more transcription factors to the list of potential downstream targets of cardiac glycoside action, including HIF1-a, Hoxb-13 and Spdef. In order to obtain a more systemic view of the molecular pathways involved, a whole genome microarray expression upon treatment with peruvoside was conducted in pancreatic cancer cell lines and potential pathways were proposed. In parallel, a microRNA screen platform was used to identify potential microRNAs involved in their mode of action. These new data provide a better understanding of the molecular mechanism of these drugs and highlight their potential future use in cancer therapies.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4621.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO