The α1 subunit of the sodium pump could represent a novel target to combat non‐small cell lung cancers

Mijatovic, Tatjana; Roland, Isabelle; Quaquebeke, Eric Van; Nilsson, Berith; Mathieu, Anne; Vynckt, Frank Van; Darro, Francis; Blanco, Gustavo; Facchini, V.; Kiss, Róbert

doi:10.1002/path.2172

Cited by 148 publications

(179 citation statements)

References 44 publications

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“…Additionally, the rodent α1 isoform is almost 1,000 times less sensitive to cardiac glycosides than that in the human due to a double mutation in the first extracellular loop (18). After the assessment of adenocarcinomas and squamous cell carcinoma tissues from 59 patients with lung cancer, Mijatovic et al suggested that the α1 isoform of Na,K-ATPase may be a useful target for cardiac glycosides in the treatment of non-small cell lung cancer cells (34). They reported that cardiac glycosides such as ouabain, digixon, and UNBS1450 showed the strongest inhibition of the rat Na,K-ATPase α3β1 isoform followed by α2β1 and α1β1 isoforms growing in sf9-insect cells.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…44) However, it seems that the α1 isoform plays a primary role in Na + / K + -ATPase and is more abundant than the other α isoforms in A549 cells, as siRNA targeting the α1 isoform markedly impaired the proliferation and migration of A549 cells for 6 d. 44) We have found that knockdown of Na It has been reported that ouabain and ouabagenin inhibit the α1β1, α2β1, and α3β1 complexes of human recombinant Na + /K + -ATPase with similar potency, although ouabagenin shows weaker inhibitory activity than ouabain.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Cardiac glycosides, which are inhibitors of Na /K -ATPase, are classified into cardenolides and bufadienolides. We have recently shown that two cardenolide glycosides, ouabain and odoroside A, inhibit Na / K -ATPase, thereby preventing nuclear factor κB-inducible protein expression by blocking Na -dependent amino acid transport. In this study, we investigated the mechanism of action of cardenolide aglycones in tumor necrosis factor α (TNF-α)-induced gene expression. Ouabagenin, digitoxigenin, and digoxigenin were found to inhibit the TNF-α-induced cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) in human lung carcinoma A549 cells. Those cardenolide aglycones did not inhibit the TNF-α-induced expression of ICAM-1 mRNA, but strongly inhibited the TNF-α-induced expression of ICAM-1 as translation product. The inhibition of the TNF-α-induced ICAM-1 expression by ouabagenin, digitoxigenin, and digoxigenin was significantly reversed by the ectopic expression of ouabain-resistant rat Na /K -ATPase α1 isoform. Moreover, knockdown of Na /K -ATPase α1 isoform augmented the inhibition of the TNF-α-induced ICAM-1 expression by ouabagenin or ouabain. These results clearly indicate that cardenolide aglycones inhibit the TNF-α-induced ICAM-1 expression at the translation step by blocking Na /K -ATPase.

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“…Recent advances in the investigation of bufadienolides have indicated that RB is a type of biologically active molecule with a wide variety of physiologic and pharmacological functions (Mijatovic et al, 2007;Newman et al, 2008). The previous studies reported that the cytotoxic and cardiotoxic action of bufadienolides varied greatly and the substituted groups of steroid skeletons could significantly influence these effects.…”

Section: Discussionmentioning

confidence: 99%

“…Many studies in recent years indicate that resibufogenin possesses significant pharmacological and toxicological effects, including cardiotonic, anesthetic, antitumor, and cardiotoxic effects. Furthermore, both preclinical and clinical studies show that RB and its analogs possess the skeletons of bufadienolide are potent anticancer agents (Mijatovic et al, 2007;Newman et al, 2008). It has been reported that RB exhibits strong cytotoxic activities against human myeloid leukemia, prostate cancer, and human hepatoma cells, with IC 50 values of approximately 10-50 nM (Kamano et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Phase I Metabolism of Resibufogenin and Evaluation of the Metabolic Effects on Its Antitumor Activity and Toxicity

Ning

et al. 2014

Drug Metab Dispos

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Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has displayed great potential as a chemotherapeutic agent in oncology. However, it is a digoxinlike compound that also exhibits extremely cardiotoxic effects. The present study aimed to characterize the metabolic behaviors of RB in humans as well as to evaluate the metabolic effects on its bioactivity and toxicity. The phase I metabolic profile in human liver microsomes was characterized systemically, and the major metabolite was identified as marinobufagenin (5b-hydroxylresibufogenin, 5-HRB) by liquid chromatography-mass spectrometry and nuclear magnetic imaging techniques. Both cytochrome P450 (P450) reaction phenotyping and inhibition assays using P450-selective chemical inhibitors demonstrated that CYP3A4 was mainly involved in RB 5b-hydroxylation with much higher selectivity than CYP3A5. Kinetic characterization demonstrated that RB 5b-hydroxylation in both human liver microsomes and human recombinant CYP3A4 obeyed biphasic kinetics and displayed similar apparent kinetic parameters. Furthermore, 5-HRB could significantly induce cell growth inhibition and apoptosis in A549 and H1299 by facilitating apoptosome assembly and caspase activation. Meanwhile, 5-HRB displayed very weak cytotoxicity of human embryonic lung fibroblasts, and in mice there was a greater tolerance to acute toxicity. In summary, CYP3A4 dominantly mediated 5b-hydroxylation and was found to be a major metabolic pathway of RB in the human liver, whereas its major metabolite (5-HRB) displayed better druglikeness than its parent compound RB. Our findings lay a solid foundation for RB metabolism studies in humans and encourage further research on the bioactive metabolite of RB.

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The α1 subunit of the sodium pump could represent a novel target to combat non‐small cell lung cancers

Cited by 148 publications

References 44 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

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

Characterization of Phase I Metabolism of Resibufogenin and Evaluation of the Metabolic Effects on Its Antitumor Activity and Toxicity

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