Actein inhibits the Na+-K+-ATPase and enhances the growth inhibitory effect of digitoxin on human breast cancer cells

Einbond, Linda Saxe; Shimizu, Masahito; Ma, Hangbao; Wu, Hsan Au; Goldsberry, Sarah; Sicular, Serge; Panjikaran, Maya; Genovese, Giannicola; Cruz, Erica

doi:10.1016/j.bbrc.2008.08.054

Cited by 37 publications

(18 citation statements)

References 15 publications

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“…In particular, in vitro studies showed that exposure of non-small lung cells, renal, pancreatic and breast cells to micromolar concentrations of digitoxin (0.5–5 μM) inhibits Na + /K + -ATPase pump activity (López-Lázaro, 2007; Newman et al, 2008), induces calcium-dependent activation of caspases and other hydrolytic enzymes (Einbond et al, 2008; Elbaz et al, 2012a), causes generation of reactive oxygen species (Prassas et al, 2011), activates the cell-cycle inhibitor p21Cip1 (Prassas et al, 2011), directs the inhibition of topoisomerase activity and hypoxia-inducible factor1a synthesis (Sun et al, 2013), and ultimately reduces viability and cell proliferation (Elbaz et al, 2012a; Menger et al, 2013). Complementary, cellular exposure to nanomolar concentrations of digitoxin (10–100 nM) leads to inhibition of (HIF-1) and topoisomerase II synthesis (Prassas et al, 2011), activation of phospholipase C (Elbaz et al, 2012a; Ho et al, 1987), phosphatidylinositol-3-kinase (PI3K) (Ho et al, 1987), tyrosine kinase (Src) (Elbaz et al, 2012a; Jagielska et al, 2009), mitogen-activated protein kinase (MAPK) (Prassas et al, 2011), affects cell cycle and anoikis (Pongrakhananon et al, 2014) inducing alternations in membrane fluidity (Larre et al, 2010; Xie and Cai, 2003), ultimately leading to cell apoptosis (Lopez-Lazaro et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells

Eldawud

Stueckle

Manivannan

et al. 2014

Biosensors and Bioelectronics

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Digitoxin belongs to a naturally occurring class of cardiac glycosides (CG); digitoxin is clinically approved for heart failure and known for its anti-cancer effects against non-small lung cancer cells (NSCLC). However, concerns associated with its narrow therapeutic index and its concentration-dependent mechanism of action are rising. Thus, before digitoxin implementation in designing and developing safer and more effective CG-based anti-cancer therapies, its pharmacological and safety profiles need to be fully elucidated. In this research we used a combinatorial approach to evaluate the anti-cancer mechanisms of digitoxin in real-time. Our approach employed a non-invasive electric cell impedance sensing technique as a proxy to monitor NSCLC behavior post-exposure to toxic, therapeutic and sub-therapeutic concentrations of the drug. By developing structure–function combinatorial relations we showed that digitoxin targets cancer cells in a time and dose-dependant manner by activating pro-apoptotic and anti-proliferative signaling cascades that results in strengthening cellular adhesion and sequestration of key regulatory proliferation protein from the nucleus.

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Section: Introductionmentioning

confidence: 99%

Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells

Eldawud

Stueckle

Manivannan

et al. 2014

Biosensors and Bioelectronics

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“…Na + /K + -ATPase is responsible for the regulation of ion homeostasis in mammalian cells by exporting three Na + in exchange for two K + . Na + /K + -ATPase is involved in cancer progression and is significant in cell adhesion and signaling (3,4). Cardiac glycosides, which inhibit Na + /K + -ATPase, have been used for treating arrhythmia and congestive heart failure for >200 years (5).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cell migration by ouabain in the A549 human lung cancer cell line

Liu

et al. 2013

Oncology Letters

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The Na+/K+-ATPase α subunit is highly expressed in malignant cells. Ouabain, a cardioactive glycoside, binds to the Na+/K+-ATPase α subunit and inhibits the activity of Na+/K+-ATPase. In the present study, the effect of ouabain on the migration of A549 cells was analyzed using the wound healing and transwell chamber migration assays. The impact of ouabain on the expression of E-cadherin, N-cadherin, vimentin, matrix metalloprotease (MMP)-2 and MMP-9 was also evaluated. Ouabain treatment not only inhibited the epidermal growth factor (EGF)-enhanced migration of A549 cells, but also inhibited the basal migration of A549 cells in the absence of EGF. Ouabain decreased the overexpression of N-cadherin and vimentin induced by EGF, and decreased the expression of MMP-2 and -9 in the presence or absence of EGF. Na+/K+-ATPase is a potent therapeutic target in lung cancer and these observations indicated that the Na+/K+-ATPase inhibitor, ouabain, retards the invasion of lung cancer cells.

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“…To better understand synergy, the example of actein, a triterpene glycoside isolated from the roots and rhizomes of Cimicifuga racemosa (black cohosh), and digitoxin, a cardiac glycoside present in the plant Digitalis purpurea, can be used. According to investigations carried out by Einbond et al [19], the inhibitory effect on Na + -K + -ATPase activity, compared with the summation effect obtained by each one administered alone, is higher when co-administered. In this case, this observation is an example of pharmacodynamic synergy because actein or digitoxin facilitates the action of the other in the same target.…”

Section: The "Modern Medicine Approach" Was Not Enoughmentioning

confidence: 98%

Pharmacological Activities of Phytomedicines: A Challenge Horizon for Rational Knowledge

2018

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Herbal drugs have been widely used throughout the course of history. Traditional knowledge based on religious beliefs and/or experience has been transmitted orally between generations. First attempts to provide scientific evidence came in the 19th century when potent compounds were first isolated. Since then, modern pharmacology theory has been assumed by phytotherapy. Scientists have tried to elucidate the molecular mechanism of each compound and, for a pharmacological indication, propose an effective and secure dose. Stepwise, clinical trials confirm the benefits of herbal drug use in therapeutics, especially for chronic diseases. However, herbal drugs exert pleiotropic effects, and there is still a need for a complete, rational, and widely accepted theory that can explain phytotherapy efficacy. The "-omics" might help with this matter. Studies of modification in the gene expression profile, the metabolome, and the physiopathological state after the administration of a herbal extract could provide relevant information that verifies herbal therapies.

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Actein inhibits the Na+-K+-ATPase and enhances the growth inhibitory effect of digitoxin on human breast cancer cells

Cited by 37 publications

References 15 publications

Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells

Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells

Inhibition of cell migration by ouabain in the A549 human lung cancer cell line

Pharmacological Activities of Phytomedicines: A Challenge Horizon for Rational Knowledge

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