Abstract
Recent studies have revealed that cardiac glycosides, such as digitalis and digoxin, have anticancer activity and may serve as lead compounds for the development of cancer treatments. The poor prognosis of hepatocellular carcinoma (HCC) patients reflects the development of resistance to current chemotherapeutic agents, highlighting the need for discovering new small-molecule therapeutics. Here, we found that lanatoside C, an anti-arrhythmic agent extracted from Digitalis lanata, inhibited the growth of HCC cells and dramatically decreased tumor volume as well as delayed tumor growth without obvious body weight loss. Moreover, lanatoside C triggered mitochondrial membrane potential (MMP) loss, activation of caspases and translocation of apoptosis-inducing factor (AIF) into the nucleus, which suggests that lanatoside C induced apoptosis through both caspase-dependent and -independent pathways. Furthermore, we discovered that lanatoside C activated protein kinase delta (PKCδ) via Thr505 phosphorylation and subsequent membrane translocation. Inhibition of PKCδ reversed lanatoside C-induced MMP loss and apoptosis, confirming that lanatoside C caused apoptosis through PKCδ activation. We also found that the AKT/mTOR pathway was negatively regulated by lanatoside C through PKCδ activation. In conclusion, we provide the first demonstration that the anticancer effects of lanatoside C are mainly attributable to PKCδ activation.
Highlights
Suggest that several cardiac glycosides has been reported to exert anticancer activity through different mechanisms, such as the SRC/EGFR/RAS/ERK signaling pathway, p21, NF-κB, AP-1, topoisomerase and HIF-1, some of which do not involve targeting the Na+/K+ ion pump[7,8,9,10,11,12]
Lanatoside C inhibited the proliferation of two different human Hepatocellular carcinoma (HCC) cell lines, Hep3B and HA22T, in a concentration-dependent manner, exhibiting 50% growth-inhibitory concentrations (GI50) of 0.12 and 0.14 μM, respectively, in sulforhodamine B assays (Fig. 1B)
These results indicate that lanatoside C is capable of inhibiting proliferation and inducing apoptosis in HCC cells
Summary
Suggest that several cardiac glycosides has been reported to exert anticancer activity through different mechanisms, such as the SRC/EGFR/RAS/ERK signaling pathway, p21, NF-κB, AP-1, topoisomerase and HIF-1, some of which do not involve targeting the Na+/K+ ion pump[7,8,9,10,11,12]. These observations suggest that cardiac glycosides could be repurposed as promising anticancer candidates. As a consequence of its crucial involvement in cell death mechanisms, PKCδis a potential therapeutic target for anticancer therapy Cardiac glycosides, such as digoxin, digitoxin and ouabain, have been used clinically to treat congestive heart failure and anti-arrhythmias. We examined the antitumor activity of lanatoside C in human HCC cells and assessed its mechanism of action, providing the first demonstration that PKCδis a key mediator of lanatoside C-induced apoptosis
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