Cardiac glycosides inhibit TNF-α/NF-κB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor

Yang, Qingfeng; Huang, Wei; Jozwik, Catherine; Lin, Yong; Glasman, Mirta; Caohuy, Hung; Srivastava, Meera; Esposito, Dominic; Gillette, William; Hartley, James L.; Pollard, Harvey B.

doi:10.1073/pnas.0504097102

Cited by 86 publications

(71 citation statements)

References 35 publications

(42 reference statements)

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“…Other investigators have reported that cardiac glycoside drugs, such as digitoxin and oleandrin, inhibit the constitutive hypersecretion of nuclear factor κB-dependent proinflammatory cytokine interleukin 8 from cystic fibrosis lung epithelial cells (13). These investigators also observed that oleandrin, as well as digoxin, suppressed the tumor necrosis factor-α/nuclear factor κB signaling pathway by blocking tumor necrosis factor-α-dependent TNFR1/TRADD complex formation (14). Oleandrin has also been shown to induce apoptosis in human leukemia cells by dephosphorylation of Akt, expression of FasL, as well as alteration of membrane fluidity (9).…”

Section: Introductionsupporting

confidence: 48%

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Yang

Menter

Cartwright

et al. 2009

Molecular Cancer Therapeutics

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Cardiac glycosides such as oleandrin are known to inhibit the Na,K-ATPase pump, resulting in a consequent increase in calcium influx in heart muscle. Here, we investigated the effect of oleandrin on the growth of human and mouse cancer cells in relation to Na,K-ATPase subunits. Oleandrin treatment resulted in selective inhibition of human cancer cell growth but not rodent cell proliferation, which corresponded to the relative level of Na,K-ATPase α3 subunit protein expression. Human pancreatic cancer cell lines were found to differentially express varying levels of α3 protein, but rodent cancer cells lacked discernable expression of this Na,K-ATPase isoform. A correlation was observed between the ratio of α3 to α1 isoforms and the level of oleandrin uptake during inhibition of cell growth and initiation of cell death; the higher the α3 expression relative to α1 expression, the more sensitive the cell was to treatment with oleandrin. Inhibition of proliferation of Panc-1 cells by oleandrin was significantly reduced when the relative expression of α3 was decreased by knocking down the expression of α3 isoform with α3 siRNA or increasing expression of the α1 isoform through transient transfection of α1 cDNA to the cells. Our data suggest that the relative lack of α3 (relative to α1) in rodent and some human tumor cells may explain their unresponsiveness to cardiac glycosides. In conclusion, the relatively higher expression of α3 with the limited expression of α1 may help predict which human tumors are likely to be responsive to treatment with potent lipid-soluble cardiac glycosides such as oleandrin.

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Section: Introductionsupporting

confidence: 48%

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Yang

Menter

Cartwright

et al. 2009

Molecular Cancer Therapeutics

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“…These other functions appear to be nonexclusive. For example, digitoxin blockade of proinf lammatory TNF-␣/NF-B signaling occurs at subnanomolar concentrations (17,18,28). This function is therefore unlikely to be dependent on digitoxin calcium channels, which only become active above a threshold of ca.…”

Section: Discussionmentioning

confidence: 99%

“…Non-NaKATPase effects also have been observed. For example, quite low subnanomolar concentrations of the cardiac glycoside digitoxin also are able to block TNF-␣/NF-B signaling (17,18). Thus, the mechanism for calcium-specific actions of digitoxin and other medicinal cardiac glycosides remains to be fully understood.…”

mentioning

confidence: 99%

Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

Arispe

Díaz

Šimáková

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Digitoxin and other cardiac glycosides are important, centuries-old drugs for treating congestive heart failure. However, the mechanism of action of these compounds is still being elucidated. Calcium is known to potentiate the toxicity of these drugs, and we have hypothesized that digitoxin might mediate calcium entry into cells. We report here that digitoxin molecules mediate calcium entry into intact cells. Multimers of digitoxin molecules also are able to form calcium channels in pure planar phospholipid bilayers. These digitoxin channels are blocked by Al 3؉ and La 3؉ but not by Mg 2؉ or the classical L-type calcium channel blocker, nitrendipine. In bilayers, we find that the chemistry of the lipid affects the kinetics of the digitoxin channel activity, but not the cation selectivity. Antibodies against digitoxin promptly neutralize digitoxin channels in both cells and bilayers. We propose that these digitoxin calcium channels may be part of the mechanism by which digitoxin and other active cardiac glycosides, such as digoxin, exert system-wide actions at and above the therapeutic concentration range.cardiac glycoside ͉ cytotoxicity

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“…Weaker edges connect two of the three tested compounds to community n. 63, consisting of Na þ ∕K þ -ATPase membrane pump inhibitors. This proximity might be explained by the fact that inhibition of Na þ ∕K þ -ATPases by cardiac glycosides has been shown to affect NF-kB signaling (31). Fuzzy GO term enrichment analysis showed that genes involved in the response to unfolded proteins are upregulated in community n. 28 and community n. 104, whereas community n. 40 is enriched for GO terms relative to endoplasmatic reticulum overload and stress.…”

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confidence: 97%

Discovery of drug mode of action and drug repositioning from transcriptional responses

Iorio

Bosotti²,

Scacheri³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A bottleneck in drug discovery is the identification of the molecular targets of a compound (mode of action, MoA) and of its off-target effects. Previous approaches to elucidate drug MoA include analysis of chemical structures, transcriptional responses following treatment, and text mining. Methods based on transcriptional responses require the least amount of information and can be quickly applied to new compounds. Available methods are inefficient and are not able to support network pharmacology. We developed an automatic and robust approach that exploits similarity in gene expression profiles following drug treatment, across multiple cell lines and dosages, to predict similarities in drug effect and MoA. We constructed a "drug network" of 1,302 nodes (drugs) and 41,047 edges (indicating similarities between pair of drugs). We applied network theory, partitioning drugs into groups of densely interconnected nodes (i.e., communities). These communities are significantly enriched for compounds with similar MoA, or acting on the same pathway, and can be used to identify the compoundtargeted biological pathways. New compounds can be integrated into the network to predict their therapeutic and off-target effects. Using this network, we correctly predicted the MoA for nine anticancer compounds, and we were able to discover an unreported effect for a well-known drug. We verified an unexpected similarity between cyclin-dependent kinase 2 inhibitors and Topoisomerase inhibitors. We discovered that Fasudil (a Rho-kinase inhibitor) might be "repositioned" as an enhancer of cellular autophagy, potentially applicable to several neurodegenerative disorders. Our approach was implemented in a tool (Mode of Action by NeTwoRk Analysis, MANTRA, http://mantra.tigem.it).computational drug discovery | drug repurposing | systems biology | chemotherapy

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Cardiac glycosides inhibit TNF-α/NF-κB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor

Cited by 86 publications

References 35 publications

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

Discovery of drug mode of action and drug repositioning from transcriptional responses

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