Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochem Biophys Rep
2016 Mar 31;6:158-164. doi: 10.1016/j.bbrep.2016.03.015.
Show Gene links
Show Anatomy links
Inhibitory efficacy of bufadienolides on Na+,K+-pump activity versus cell proliferation.
Xu Y
,
Liu X
,
Schwarz S
,
Hu L
,
Guo D
,
Gu Q
,
Schwarz W
.
???displayArticle.abstract???
Bufadienolides are cytotoxic drugs that may form the basis for anticancer agents. Due to structural and functional similarity to cardiotonic glycosides, application is restricted. We, therefore, investigated correlation of their putative anticancer effects with inhibition of Na+,K+pumps. The natural bufalin and three derivatives were tested. The anticancer effects of the drugs were checked by observing their inhibitory effects on proliferation of rat liver cancer cells using MTT assay. Inhibition of Na+,K+-pump was determined by measuring pump-mediated current of rat α1/β1 and α2/β1 Na+,K+pumps expressed in Xenopus oocytes. All tested bufadienolides inhibited cell proliferation and Na+,K+pump activity. An activity coefficient A=100xIC
50
Na,K pump/IC50proliferation was used to describe drug effectivity as anticancer drug. Natural bufalin exhibited lowest effectivity on cell proliferation, and also the A value for rat α1 isoform was the lowest (0.08), the α2 isoform was much less sensitive (A=1.00). The highest A values were obtained for the BF238 derivative with A=0.88 and 2.64 for the α1 and α2 isoforms, respectively. Therefore, we suggest that search for bufalin derivatives with high anticancer effect and low affinity for both Na+,K+pump isoforms may be a promising strategy for development of anticancer drugs.
Fig. 1. Dependence of viability of RH-35 cells on concentration of bufalin (open squares) and BF238 (open circles). Data represent averages + SEM (N=3). Dashed lines are approximations of euq. 1 with n=1, Y0=1, yielding IC50 values of 257.0 and 37.4 µM for bufalin and BF238, respectively.
Fig. 2. Dependence of endogenous Na+,K+pump current on concentration of bufadienolides. (A, B) Current-voltage dependencies in the absence (filled squares) and during application of 0.05 µM bufalin (open squares) and 0.05 µM BF238 (open circles), respectively. Data represent averages of N=5 oocytes + SEM. (C) Concentration-dependent inhibition of endogenous Na+,K+pump current by bufalin (open squares) and BF238 (open circles). Data represent averages of 5â10 measurements + SEM. Dashed lines are fits of euq. 1 with n=0.81, yielding IC50 values of 0.063 and 0.021 µM, respectively (compare dashed lines).
Fig. 3. Dependencies of Na+,K+pump current in oocytes with additionally expressed rat Rα1/Ã1 pumps. (A, B) Current-voltage dependencies in the absence (filled squares) and during application of 0.05 µM bufalin (open squares) and 0.05 µM BF238 (open circles), respectively. Data represent averages of N=6 oocytes + SEM. (C) Concentration-dependent inhibition of endogenous Na+,K+pump current by bufalin (open squares) and BF238 (open circles). Data represent averages of 5â10 measurements + SEM. Solid lines are fits of euq. 1 with n=0.8, yielding IC50 values of 0.215 and 0.329 µM, respectively (compare dashed lines).
Fig. 4. Dependencies of Na+,K+pump current in oocytes with additionally expressed rat Rα2/Ã1 pumps. (A, B) Current-voltage dependencies in the absence (filled squares) and during application of 0.05 and 0.5 µM bufalin (open squares and circles) and 0.05 and 0.5 µM BF 238 (open circles and rhombs). Data represent averages of N=6 oocytes + SEM. (C) Concentration-dependent inhibition of endogenous Na+,K+pump current by bufalin (open squares) and BF238 (open circles). Data represent averages of 5â10 measurements + SEM. Solid lines are fits of euq. 1 with n=0.8, yielding IC50 values of 2.558 and 0.987 µM, respectively (compare dashed lines).
Abeywardena,
Species variation in the ouabain sensitivity of cardiac Na+/K+-ATPase. A possible role for membrane lipids.
1984, Pubmed
Abeywardena,
Species variation in the ouabain sensitivity of cardiac Na+/K+-ATPase. A possible role for membrane lipids.
1984,
Pubmed
Akera,
The effect of ouabain on sodium- and potassium-activated adenosine triphosphatase from the hearts of several mammalian species.
1969,
Pubmed
Alevizopoulos,
Na+/K+ ATPase inhibitors in cancer.
2014,
Pubmed
Aronsen,
Cardiac sodium transport and excitation-contraction coupling.
2013,
Pubmed
Bick,
Effects of Chan Su, a traditional Chinese medicine, on the calcium transients of isolated cardiomyocytes: cardiotoxicity due to more than Na, K-ATPase blocking.
2002,
Pubmed
Despa,
Na(+)/K)+)-ATPase α2-isoform preferentially modulates Ca2(+) transients and sarcoplasmic reticulum Ca2(+) release in cardiac myocytes.
2012,
Pubmed
Dostanic-Larson,
Physiological role of the alpha1- and alpha2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site.
2006,
Pubmed
Fambrough,
Analysis of subunit assembly of the Na-K-ATPase.
1994,
Pubmed
Feng,
ER stress-mediated apoptosis induced by celastrol in cancer cells and important role of glycogen synthase kinase-3β in the signal network.
2013,
Pubmed
Geering,
The functional role of the beta-subunit in the maturation and intracellular transport of Na,K-ATPase.
1991,
Pubmed
,
Xenbase
Glitsch,
Electrophysiology of the sodium-potassium-ATPase in cardiac cells.
2001,
Pubmed
Gupta,
Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis).
1986,
Pubmed
Hashimoto,
Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs.
1997,
Pubmed
Hu,
Preparation of bufalin-loaded pluronic polyetherimide nanoparticles, cellular uptake, distribution, and effect on colorectal cancer.
2014,
Pubmed
James,
Identification of a specific role for the Na,K-ATPase alpha 2 isoform as a regulator of calcium in the heart.
1999,
Pubmed
Juhaszova,
Na+ pump low and high ouabain affinity alpha subunit isoforms are differently distributed in cells.
1997,
Pubmed
Juhaszova,
Distinct distribution of different Na+ pump alpha subunit isoforms in plasmalemma. Physiological implications.
1997,
Pubmed
Kawazoe,
Induction of apoptosis by bufalin in human tumor cells is associated with a change of intracellular concentration of Na+ ions.
1999,
Pubmed
Krenn,
Bufadienolides from animal and plant sources.
1998,
Pubmed
Lafaire,
Voltage dependence of the rheogenic Na+/K+ ATPase in the membrane of oocytes of Xenopus laevis.
1986,
Pubmed
,
Xenbase
Lefranc,
Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells.
2008,
Pubmed
Lingrel,
Na+,K(+)-ATPase.
1994,
Pubmed
Liu,
Imidazole inhibits autophagy flux by blocking autophagic degradation and triggers apoptosis via increasing FoxO3a-Bim expression.
2015,
Pubmed
Liu,
The sodium pump and cardiotonic steroids-induced signal transduction protein kinases and calcium-signaling microdomain in regulation of transporter trafficking.
2010,
Pubmed
Ma,
Synthesis and structure-activity relationships study of cytotoxic bufalin 3-nitrogen-containing-ester derivatives.
2013,
Pubmed
Mansier,
CA2+-free perfusion of rat heart reveals a (Na+ + K+)ATPase form highly sensitive to ouabain.
1982,
Pubmed
Meng,
Pilot study of huachansu in patients with hepatocellular carcinoma, nonsmall-cell lung cancer, or pancreatic cancer.
2009,
Pubmed
Mijatovic,
The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers.
2007,
Pubmed
Mijatovic,
Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways.
2013,
Pubmed
Prassas,
Novel therapeutic applications of cardiac glycosides.
2008,
Pubmed
Qin,
Efficacy and safety of gemcitabine-oxaliplatin combined with huachansu in patients with advanced gallbladder carcinoma.
2008,
Pubmed
Rakowski,
A negative slope in the current-voltage relationship of the Na+/K+ pump in Xenopus oocytes produced by reduction of external [K+].
1991,
Pubmed
,
Xenbase
Schoner,
Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth.
2007,
Pubmed
Schwarz,
Structure-function relationships of Na+/K(+)-pumps expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
SKOU,
The influence of some cations on an adenosine triphosphatase from peripheral nerves.
1957,
Pubmed
Steyn,
Bufadienolides of plant and animal origin.
1998,
Pubmed
Suñol,
Immunohistochemical analyses of alpha1 and alpha3 Na+/K+-ATPase subunit expression in medulloblastomas.
2011,
Pubmed
Sweadner,
Rat cardiac ventricle has two Na+,K+-ATPases with different affinities for ouabain: developmental changes in immunologically different catalytic subunits.
1987,
Pubmed
Sweadner,
Two forms of the Na,K-ATPase catalytic subunit detected by their immunological and electrophoretic differences. Alpha and alpha+ in mammalian heart.
1988,
Pubmed
Terracciano,
Rapid inhibition of the Na+-K+ pump affects Na+-Ca2+ exchanger-mediated relaxation in rabbit ventricular myocytes.
2001,
Pubmed
Vasilets,
RNA from heart of young and old rats leads to the expression of protein(s) in Xenopus oocytes that alter the transport activity of rat Na+,K+-ATPases differently.
2001,
Pubmed
,
Xenbase
Vasilets,
Structure-function relationships of cation binding in the Na+/K(+)-ATPase.
1993,
Pubmed
Xie,
Na(+)/K(+)-ATPase as a signal transducer.
2002,
Pubmed
Yeh,
Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells.
2003,
Pubmed
Yin,
Anti-tumor activity and apoptosis-regulation mechanisms of bufalin in various cancers: new hope for cancer patients.
2012,
Pubmed
Yin,
Bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles: preparation, cellular uptake, tissue distribution, and anticancer activity.
2012,
Pubmed
Yoshimura,
Fast degradation of the auxiliary subunit of Na+/K+-ATPase in the plasma membrane of HeLa cells.
2008,
Pubmed
