Cytotoxicity Of Digoxin And Its Synthetic Derivatives

Digoxin (1), a cardiac glycoside isolated from Digitalis lanata Ehrh. has been long used to treat congestive heart failure. When tested in an early drug repurposing study, this agent was found to show anticancer activity [1]. In a search for anticancer agents from higher plants, digoxin showed activity and was selected as an anticancer lead. It exhibited potent cytotoxicity toward the HT-29 human colon cancer cells in a 72-hour incubation with an IC₅₀ value of 380 nM, and toward the human MV4; 11, THP-1, and Kasumi-1 myeloid leukemia cell lines and H1299 human non-small cell lung cancer cell line in a 48-hour incubation with IC₅₀ values of 100, 59, 89, and 62 nM, respectively. Interestingly, when tested toward the normal human cell lines, digoxin showed much lower activity. It exhibited cytotoxicity toward the CCD-112CoN human normal colon cells that was ten-fold lower than toward the HT-29 cells. Also, it showed relatively little cytotoxicity toward normal human peripheral blood mononuclear cells in 48 hours under these same conditions. Several synthetic derivatives of digoxin have been prepared and evaluated, and both the C-12 and C-14 hydroxy group and the C-17 lactone ring were found critical for this agent to mediate cytotoxicity toward HT-29 cells, but the C-3 glycosyl residue is not necessary for this effect.

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Reference: [1] Cragg, GM, Grothaus PG, Newman DJ. (2014) Journal of Natural Products, 77: 703 – 723.