Cardenolide Aglycones Inhibit Tumor Necrosis Factor α-Induced Expression of Intercellular Adhesion Molecule-1 at the Translation Step by Blocking Na+/K+-ATPase

Okina, Yuji; Takeuchi, Fumihiko; Yokomichi, Tomonobu; Takada, Yuji; Kataoka, Takao

doi:10.1248/bpb.b14-00532

Cited by 5 publications

(3 citation statements)

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“…Although plenty of reports about the anti-cancer function of digitalis have been published, few articles about EGFR T790M/L858R were on digoxin [41] and ouabain [38]. In NSCLC, many studies were mostly focused on A549 [38,41,44,45,46,47,48,49,50,51,52] and H460 cells with WT EGFR [41,43,53,54]. To our knowledge, no research report has addressed the effect of Digitoxin on Gefitinib resistant EGFR T790M/L858R mutated H1975 cells.…”

Section: Discussionmentioning

confidence: 99%

Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation

et al. 2016

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Non-small-cell lung cancer (NSCLC) dominates over 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) activating mutation is a common situation in NSCLC. In the clinic, molecular-targeting with Gefitinib as a tyrosine kinase inhibitor (TKI) for EGFR downstream signaling is initially effective. However, drug resistance frequently happens due to additional mutation on EGFR, such as substitution from threonine to methionine at amino acid position 790 (T790M). In this study, we screened a traditional Chinese medicine (TCM) compound library consisting of 800 single compounds in TKI-resistance NSCLC H1975 cells, which contains substitutions from leucine to arginine at amino acid 858 (L858R) and T790M mutation on EGFR. Attractively, among these compounds there are 24 compounds CC 50 of which was less than 2.5 µM were identified. We have further investigated the mechanism of the most effective one, Digitoxin. It showed a significantly cytotoxic effect in H1975 cells by causing G2 phase arrest, also remarkably activated 5 1 adenosine monophosphate-activated protein kinase (AMPK). Moreover, we first proved that Digitoxin suppressed microtubule formation through decreasing α-tubulin. Therefore, it confirmed that Digitoxin effectively depressed the growth of TKI-resistance NSCLC H1975 cells by inhibiting microtubule polymerization and inducing cell cycle arrest.

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Section: Discussionmentioning

confidence: 99%

Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation

et al. 2016

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“…It is known that bufadienolides specifically inhibit sodium pump (Na + /K + -ATPase) [22], whose main function unit is α subunit. Among all four components of α subunit, α1 subunit is found to be higher expression in human glioma tissues than normal tissue [23] and was generally thought to be a potential target for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Marinobufagenin inhibits glioma growth through sodium pump α1 subunit and ERK signaling‐mediated mitochondrial apoptotic pathway

et al. 2018

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Malignant glioma is one of the most challenging central nervous system diseases to treat and has high rates of recurrence and mortality. Current therapies often fail to control tumor progression or improve patient survival. Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid involved in sodium pump inhibition. Currently, various studies have indicated the potential of MBG in cancer treatments; however, the precise mechanisms are poorly understood. The functions of MBG were examined using colony formation, migration, cell cycle, and apoptosis assays in glioma cells. A mitochondrial membrane potential assay was performed to determine the mitochondrial transmembrane potential change, and cytochrome c release from mitochondria was assayed by fluorescence microscopy. An immunofluorescence assay was performed, and the nuclear translocation of NF‐κB in glioma cells was confirmed by confocal microscopy. Western blotting and RT‐qPCR were used to detect the protein and gene expression levels, respectively. In addition, transfection experiment of ATP1A1‐siRNA was further carried out to confirm the role of sodium pump α1 subunit in the anticancer effect of MBG in human glioma. The apoptosis‐promoting and anti‐inflammatory effects of MBG were further investigated, and the sodium pump α1 subunit and the ERK signaling pathway were found to be involved in the anticancer effect of MBG. The in vivo anticancer efficacy of MBG was also tested in xenografts in nude mice. Thus, therapies targeting the ERK signaling‐mediated mitochondrial apoptotic pathways regulated by MBG might represent potential treatments for human glioma, and this study could accelerate the finding of newer therapeutic approaches for malignant glioma treatment.

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“…mRNA Expression Assay ICAM-1 mRNA expression was evaluated by Real-Time PCR as described previously, 17) except for primers: 5′-GCC TGG GAA CAA CCG GAA GGT G-3′ and 5′-GGGTGCCAGTTCCACCCGTTC-3′ for the 148-bp fragment of ICAM-1 18) and 5′-GGA CAT CCG CAA AGA CCT GTA-3′ and 5′-GCT CAG GAG GAG CAA TGA TCT-3′ for the 143-bp fragment of β-actin 19) and PCR conditions: 94°C for 3 min, followed by 45 cycles of 95˚C for 5 s, 58°C for 30 s, and 72°C for 30 s.…”

Section: Methodsmentioning

confidence: 99%

Eudesmane-Type Sesquiterpene Lactones Inhibit Nuclear Translocation of the Nuclear Factor κB Subunit RelB in Response to a Lymphotoxin β Stimulation

Quach

Kondo

Watanabe

et al. 2017

Biological & Pharmaceutical Bulletin

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The transcription factor nuclear factor κB (NF-κB) regulates various biological processes, including inflammatory responses. We previously reported that eudesmane-type sesquiterpene lactones inhibited multiple steps in the canonical NF-κB signaling pathway induced by tumor necrosis factor-α and interleukin-1α. In contrast, the biological activities of eudesmane-type sesquiterpene lactones on the non-canonical NF-κB signaling pathway remain unclear. In the present study, we found that (11S)-2α-bromo-3-oxoeudesmano-12,6α-lactone, designated santonin-related compound 2 (SRC2), inhibited NF-κB luciferase reporter activity induced by lymphotoxin β (LTβ) in human lung carcinoma A549 cells. Although SRC2 did not prevent the processing of the NF-κB subunit p100 induced by LTβ, it inhibited the nuclear translocation of RelB and p52 in response to the LTβ stimulation. In contrast to ( )-dehydroxymethylepoxyquinomicin, SRC2 inhibited the LTβ-induced nuclear translocation of the RelB (C144S) mutant in a manner similar to wild-type RelB. While eudesmane derivatives possessing an α-bromoketone moiety or α,β-unsaturated carbonyl moieties inhibited LTβ-induced NF-κB luciferase reporter activity, eudesmane derivatives possessing an α-bromoketone moiety exhibited stronger inhibitory activity on the LTβ-induced nuclear translocation of RelB than those possessing a single α-methylene-γ-lactone moiety. The results of the present study revealed that SRC2 inhibits the nuclear translocation of RelB in the non-canonical NF-κB signaling pathway induced by LTβ.Key words eudesmane; lymphotoxin β; nuclear factor κB; RelB; sesquiterpene lactone Nuclear factor κB (NF-κB) is a family of structurally-related eukaryotic transcription factors that regulate the expression of a number of important genes, including those related to cell proliferation, cell death, and inflammation.1) The NF-κB family consists of five subunits: RelA(p65), RelB, c-Rel, p105/p50, and p100/p52. 2)Various types of stimuli, including inflammatory cytokines, activate the canonical and non-canonical NF-κB signaling pathways.3) In the canonical NF-κB pathway, tumor necrosis factor (TNF) family members, such as TNF-α, induce the activation of the inhibitor of NF-κB (IκB) kinase β. 4) In the cytosol, IκB sequesters the NF-κB heterodimers RelA and p50 and prevents their nuclear translocation. 4) Upon phosphorylation, IκB undergoes ubiquitination and proteasomal degradation, leading to the liberation and nuclear translocation of the RelA and p50 heterodimers. 5) In contrast, the non-canonical NF-κB pathway is triggered by other TNF family members, such as lymphotoxin β (LTβ).6) The NF-κB subunits RelB and p100/p52 play essential roles in the non-canonical NF-κB pathway. 7) In unstimulated cells, p100 constitutively associates with RelB in the cytosol and inhibits its activity.7) Upon a stimulation with LTβ, IκB kinase α is primarily activated and then directly phosphorylates p100.3) Phosphorylated p100 is ubiquitinated and processed into p52 by proteasome, leading to the nuclear ...

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Cardenolide Aglycones Inhibit Tumor Necrosis Factor α-Induced Expression of Intercellular Adhesion Molecule-1 at the Translation Step by Blocking Na+/K+-ATPase

Cited by 5 publications

References 47 publications

Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation

Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation

Marinobufagenin inhibits glioma growth through sodium pump α1 subunit and ERK signaling‐mediated mitochondrial apoptotic pathway

Eudesmane-Type Sesquiterpene Lactones Inhibit Nuclear Translocation of the Nuclear Factor κB Subunit RelB in Response to a Lymphotoxin β Stimulation

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