Cardiac glycosides: From molecular targets to immunogenic cell death

Diederich, Marc; Müller, Florian; Cerella, Claudia

doi:10.1016/j.bcp.2016.08.017

Cited by 87 publications

(100 citation statements)

References 64 publications

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“…It has previously been reported that cardiac glycosides have anti-cancer effects by targeting Na + /K + -ATPase 25, 26 . Via a western blot analysis, we found that the hESCs expressed Na + /K + -ATPase more abundantly than adult stem cells, such as human bone marrow mesenchymal stem cells (hBMMSCs) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Elimination of undifferentiated human embryonic stem cells by cardiac glycosides

Lin

Wang

Yang

et al. 2017

Sci Rep

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An important safety concern in the use of human pluripotent stem cells (hPSCs) is tumorigenic risk, because these cells can form teratomas after an in vivo injection at ectopic sites. Several thousands of undifferentiated hPSCs are sufficient to induce teratomas in a mouse model. Thus, it is critical to remove all residue-undifferentiated hPSCs that have teratoma potential before the clinical application of hPSC-derived cells. In this study, our data demonstrated the cytotoxic effects of cardiac glycosides, such as digoxin, lanatoside C, bufalin, and proscillaridin A, in human embryonic stem cells (hESCs). This phenomenon was not observed in human bone marrow mesenchymal stem cells (hBMMSCs). Most importantly, digoxin and lanatoside C did not affect the stem cells’ differentiation ability. Consistently, the viability of the hESC-derived MSCs, neurons, and endothelium cells was not affected by the digoxin and lanatoside C treatment. Furthermore, the in vivo experiments demonstrated that digoxin and lanatoside C prevented teratoma formation. To the best of our knowledge, this study is the first to describe the cytotoxicity and tumor prevention effects of cardiac glycosides in hESCs. Digoxin and lanatoside C are also the first FDA-approved drugs that demonstrated cytotoxicity in undifferentiated hESCs.

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Section: Resultsmentioning

confidence: 99%

Elimination of undifferentiated human embryonic stem cells by cardiac glycosides

Lin

Wang

Yang

et al. 2017

Sci Rep

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“…More recently a correlation between CG intake and anticancer activity was suggested, further validated by in vivo and in vitro preclinical research. Our recent findings demonstrate that CGs efficiently act on cancer cell proliferation and survival [1]. UNBS1450 is a hemi-synthetic cardenolide that exerts cytostatic and cytotoxic effects in leukemia and solid tumors at low micromolar concentrations.…”

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confidence: 88%

Cardiac Glycosides as Novel Modulators of Cancer Cell Survival

Diederich

2017

Proceedings of the 2nd International Conference on Natural Products for Cancer Prevention and Therapy

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Cardiac glycosides (CGs) were initially described as a cure for cardiovascular diseases. More recently a correlation between CG intake and anticancer activity was suggested, further validated by in vivo and in vitro preclinical research. Our recent findings demonstrate that CGs efficiently act on cancer cell proliferation and survival [1]. UNBS1450 is a hemi-synthetic cardenolide that exerts cytostatic and cytotoxic effects in leukemia and solid tumors at low micromolar concentrations. In leukemia, downregulation of Mcl-1 was observed after 4 hours of treatment in the absence of any effect at the transcriptional level. By generalizing our observations with cardenolides and bufadienolides of different plant and animal origins, we showed that Mcl1can be considered as a universal target for CGs in cancer. Moreover, we demonstrated that Mcl-1 degradation is proteasome-dependent preceding apoptotic cell death. Furthermore, UNBS140 also triggers autophagy and mitophagy in solid tumors like neuroblastoma. So far, UNBS1450 was shown to trigger both complete and incomplete mitophagy in neuroblastoma leading to necroptosis and apoptosis, respectively [2], depending on the subtype of neuroblastoma. In AML, a combination of UNBS1450 and BH3 mimetics like ABT199 or 263 affects leukemia subtypes relying on Mcl-1 expression [3]. Altogether CGs are interesting pharmacological agents that efficiently induce cell death in cancer cell models at nanomolar concentrations encouraging us to further explore the therapeutic potential for CGs alone or in combination with other targeted treatments. Conflicts of Interest:The authors declare no conflict of interest.

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“…Structural analysis by MS and NMR spectral data and chemical evidence show that ToxH is a cardiac glycoside with a special cardenolide structure ( Figure 1A) [15]. Recent research results indicate that cardenolides extracted from natural sources can have anticancer activity and can block tumor cell proliferation and induce tumor apoptosis via the regulation of several cell signaling pathways and sodium pump inhibition [16][17][18][19], and even through the induction of immunogenic cell death [20][21][22]. At this time, the anticancer activity of cardenolides has not been linked to mitophagy.…”

Section: Introductionmentioning

confidence: 99%

Toxicarioside H induces drug-resistant mitophagy via promoting expression of sirtuin-3 in lung cancer cells

Huang¹,

Sun²,

Yang³

et al. 2018

Oncotarget

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Cardenolides may have anticancer effects and toxicarioside H (ToxH), which we isolated, may have similar activity but its underlying mechanism against tumors is not clear. Herein, we report that ToxH treatment inhibited cell proliferation and induced mitochondrion-dependent apoptosis and mitophagy in human A549 and H460 lung cancer cells. ToxH treatment increased the expression of Sirt3, and inhibited Sirt3 expression via RNA interference against Sirt3 (siSirt3) suppressed mitophagy in ToxH-treated lung cancer cells. Stronger inhibition of cell proliferation and induction of apoptosis occurred when ToxH-mediated mitophagy was blocked by siSirt3. In addition, ToxH treatment redistributed hexokinase II from the mitochondria to the cytosol in A549 and H460 lung cancer cells, and decreased interaction of hexokinase II with VDAC1 was accompanied by the increased interaction of VDAC1 with parkin. Moreover, the disruption of Sirt3 by siSirt3 decreased the association of VDAC1 with parkin. Thus, ToxH induces drug-resistant mitophagy by enhancing the expression of Sirt3, which leads to the dissociation of hexokinase II from VDAC1 and increased binding of VDAC1 with parkin. Adding ToxH to a mitophagy inhibitor may thus be an effective strategy for treating lung cancer.

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Cardiac glycosides: From molecular targets to immunogenic cell death

Cited by 87 publications

References 64 publications

Elimination of undifferentiated human embryonic stem cells by cardiac glycosides

Elimination of undifferentiated human embryonic stem cells by cardiac glycosides

Cardiac Glycosides as Novel Modulators of Cancer Cell Survival

Toxicarioside H induces drug-resistant mitophagy via promoting expression of sirtuin-3 in lung cancer cells

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