Abstract

In light of the incidental and remarkable findings of the putative anticancer efficacy of digitalis glycosides in the treatment and relapse prevention of different human cancers, we have explored Acovenoside A (AcoA), a member of the cardenolide glycoside family that has been hardly investigated so far, with respect to its putative effects on tumor cells at the molecular level as well as its impact on tumor growth. Of note, at equimolar concentrations, AcoA inhibited the proliferation and induced cell cycle arrest of A549 lung cancer cells more efficiently than the approved and commonly used chemotherapeutic drug doxorubicin, whereas non‐tumorous peripheral blood mononuclear cells remained unaffected. The detection of increased amounts of caspase‐3‐ and annexin V‐positive cells indicated canonical apoptosis as the main form of the AcoA‐driven cancer cell‐specific toxicity. These in vitro findings were confirmed in a preclinical model of lung cancer xenografts grown on chorioallantoic membranes (CAMs) of fertilized chick eggs used as an in vivo model. Thus, after repeated topical application, AcoA treated xenografts expressed less green fluorescent protein and contained a significantly lower fraction of Ki‐67‐positive proliferative cells, but a higher proportion of apoptotic TdT‐positive cells indicating inhibition of proliferation and induction of apoptosis in vivo. Tumor cells loaded with a fluorescent sodium indicator exhibited an increased concentrations of cytosolic sodium ion upon AcoA treatment pointing to the inhibition of the Na+‐K+‐ATPase complex as the major cellular target of AcoA. Inhibition of the Na+‐K+‐ATPase complex in tumor cells by AcoA resulted in a reduced phosphorylation of Src kinase and Aurora kinase A playing important roles in tumor growth and metabolism. Similarly, AcoA strongly inhibited the TNF‐α induced activation of NF‐κB and the IFN‐α induced activation of the interferon regulatory factor 3 known to be involved in tumor survival pathways.Our findings on the inhibition of pathways, which are important in cancer cells, corroborate AcoA as a potent member of the cardenolide glycoside family. Based on its pharmacodynamics effects, the compound deserves further exploration as a potential anticancer drug.

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