Cellular location and expression of Na<sup>+</sup>, K<sup>+</sup>-ATPase α subunits affect the anti-proliferative activity of oleandrin

Yang, Peiying; Cartwright, Carrie; Efuet, Ekem T.; Hamilton, Stanley R.; Wistuba, Ignacio I.; Menter, David G.; Addington, Crandell; Shureiqi, Imad; Newman, Robert A.

doi:10.1002/mc.21968

Cited by 35 publications

(30 citation statements)

References 42 publications

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“…Similarly, the distribution of 3 isoform was shifted from the cytoplasmic membrane location in differentiated human colon cancer CaCO-2 cells to a perinuclear position in undifferentiated CaCO-2 cells. This fact points up the significance of changes in the locality of Na + /K + -ATPase and their possible use in cancer therapy [205].…”

Section: Role Of Na + /K + -Atpase In Tumor Cells and Its Directionmentioning

confidence: 87%

From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment

Babula¹,

Masařík²,

Adam³

et al. 2013

ACAMC

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The cardiac glycosides are a group of compounds isolated from plants and some animals. They have been used in therapy for heart failure for many years. The cytotoxic effect of many cardiac glycosides has been demonstrated, but the mechanism of action is very complicated and complex, and Na+/K+-ATPase surely plays a crucial role in it. On the other hand, Na+/K+-ATPase is regulated by many endogenous factors, such as hormones or FXYD proteins, whose role in regulating the cell cycle has been studied intensively. This review focuses on the role of Na+/K+-ATPase in regulating the cell growth, the cell cycle and the cell proliferation and on the involvement of cardiac glycosides in regulating Na+/K+-ATPase. The cytotoxic effect of cardiac glycosides is discussed with respect to the apoptotic mechanisms possibly induced by these compounds. Novel strategies in cancer therapy based on cardiac glycosides are discussed as are possibilities for counteracting multidrug resistance by using cardiac glycosides. The aim of this review is to present cardiac glycosides not only as pharmaceuticals used in the management of heart failure, but also as potent cytotoxic agents with potential uses in cancer treatment.

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Section: Role Of Na + /K + -Atpase In Tumor Cells and Its Directionmentioning

confidence: 87%

From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment

Babula¹,

Masařík²,

Adam³

et al. 2013

ACAMC

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“…20 In fact, differences in the isoforms of Na + /K + -ATPase located between normal and malignant cells determine its binding capability. 21 The data obtained in the present study demonstrate that murine cells are more resistant to cardiac glycosides than human cells, regardless of whether they were considered normal or malignant. Notably, (+)-strebloside and digitoxin show different cytotoxicity in HGSC and normal cells, with normal cells being more susceptible.…”

Section: Resultsmentioning

confidence: 47%

(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks

Chen

Ren

et al. 2017

J. Nat. Prod.

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(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis, indicated that (+)-strebloside binds and inhibits Na+/K+-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2-phase and induced PARP cleavage indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.

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“…In agreement with this Na + /K + -ATPase α subunits are strongly expressed in the intracellular compartment of MCF-7 cells [3]. Intracellular distribution of overexpressed α subunits also occurs in cancer cells of other tissues [24,25]. We are not aware of reports of parallel intracellular expression of α/ β subunits to implicate expression of functional Na + /K + -ATPase.…”

Section: Discussionmentioning

confidence: 62%

Na+/K+-ATPase-associated FXYD3 Protein As An Intracellular Therapeutic Target in Cancer

Liu

Kim

Teh

et al. 2020

Preprint

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BackgroundFXYD proteins associate closely with- and protect plasmalemmal Na+/K+-ATPase against oxidative inhibition. One of them, FXYD3, is often overexpressed in cancers, including those of breast and pancreas. Down-regulation of overexpression in MCF-7 breast cancer cells with siRNA augments doxorubicin-induced cytotoxicity. Because down-regulation with siRNA is not readily translated therapeutically, we developed a peptide as an alternative for suppression of FXYD3.MethodsA shortened peptide derivative of the wild-type (WT) FXYD3 protein, FXYD3-pep has the four cysteine residues in the WT protein replaced by serine, which eliminates the WT protein’s protection against oxidative Na+/K+-ATPase inhibition. We exposed human cancer cells to FXYD3-pep and measured cytotoxicity and caspase 3/7 activity with co-exposure to doxorubicin. We also measured effects of the peptide on expression glutathione-S-transferase π (GST-π), implicated in treatment resistance, and on expression of tumor suppressor p53. Selected experiments were performed with parallel FXYD3 suppression with siRNA or FXYD3-pep.ResultsExposure of cells to FXYD3-pep displaced WT FXYD3 from Na+/K+-ATPase. Exposure of MCF-7 breast or pancreatic BxPC-3 cancer cells that highly express FXYD3 to the peptide had little effect alone but combined with doxorubicin it significantly (P < 0.05) increased cytotoxicity. A peptide not mutated to eliminate FXYD3’s protective effect of Na+/K+-ATPase had no effect. FXYD3-pep did not augment doxorubicin’s cytotoxicity against MDA-MB-468 breast and Panc-1 pancreatic cancer cells that have low- or no FXYD3 expression. Cellular FXYD3 expressions was reflected by expression of the α1 Na+/K+-ATPase subunits but not by plasmalemmal Na+/K+-ATPase function. Signals from fluorescently labeled FXYD3-pep were detected in a perinuclear distribution in BxPC-3 cells as reported for overexpressed FXYD3, α- and β Na+/K+-ATPase subunits in cancer. Exposure to FXYD3-pep or to FXYD3 siRNA almost eliminated expression of GST-π. FXYD3-pep alone had no effect on p53 levels but significantly augmented a doxorubicin-induced increase, and, while the peptide alone had no effect on caspase 3/7 activity, it significantly augmented a doxorubicin-induced increase. ConclusionsOverexpressed FXYD3 has intracellular roles beyond its accepted modulation of plasmalemmal Na+/K+-ATPase. These roles can be countered with a membrane-permeable peptide derivative of FXYD3 that suppresses GST-π and enhances chemosensitivity of cancer cells overexpressing FXYD3.

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Cellular location and expression of Na⁺, K⁺-ATPase α subunits affect the anti-proliferative activity of oleandrin

Cited by 35 publications

References 42 publications

From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment

From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment

(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks

Na+/K+-ATPase-associated FXYD3 Protein As An Intracellular Therapeutic Target in Cancer

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Cellular location and expression of Na+, K+-ATPase α subunits affect the anti-proliferative activity of oleandrin

Cited by 35 publications

References 42 publications

From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment

From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment

(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks

Na+/K+-ATPase-associated FXYD3 Protein As An Intracellular Therapeutic Target in Cancer

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Cellular location and expression of Na⁺, K⁺-ATPase α subunits affect the anti-proliferative activity of oleandrin