WordNet

of or relating to the heart; "cardiac arrest"
a group of compounds derived from monosaccharides
the opening into the stomach and that part of the stomach connected to the esophagus

PrepTutorEJDIC

心臓の

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/28 09:50:57」(JST)

wiki en

Cardiac glycosides^[1] are organic compounds containing a glycoside (sugar) that act on the contractile force of the cardiac muscle. Because of their potency in disrupting the function of the heart, most are extremely toxic. These glycosides are found as secondary metabolites in several plants, but also in some insects, such as the milkweed butterflies.

Example of the chemical structure of oleandrin, a potent toxic cardiac glycoside extracted from the Oleander bush.

Chemically, the aglycone [non-sugar] part of cardiac glycoside is a steroidal moiety.

Uses

From ancient times, humans have used cardiac-glycoside-containing plants and their crude extracts as arrow coatings, homicidal or suicidal aids, rat poisons, heart tonics, diuretics and emetics. In modern times, purified extracts or synthetic analogues of a few have been adapted for the treatment of congestive heart failure and cardiac arrhythmia.

Therapeutic uses of cardiac glycosides primarily involve the treatment of cardiac failure. Their utility results from an increased cardiac output by increasing the force of contraction. By increasing intracellular calcium as described below, cardiac glycosides increase calcium-induced calcium release and thus contraction.

Bufalin, ouabain and digoxin are a few toxic cardiac glycosides. Digoxin from the foxglove plant is used clinically, whereas bufalin and ouabain are used only experimentally due to their extremely high potency.

Pharmacology

Normally, sodium-potassium pumps in the membrane of cells (in this case, cardiac myocytes) pump potassium ions in and sodium ions out. Cardiac glycosides inhibit this pump by stabilizing it in the E2-P transition state, so that sodium cannot be extruded: intracellular sodium concentration therefore increases. A second membrane ion exchanger, NCX, is responsible for 'pumping' calcium ions out of the cell and sodium ions in (3Na/Ca); raised intracellular sodium levels inhibit this pump, so calcium ions are also not extruded and will begin to build up inside the cell, as well.

Increased cytoplasmic calcium concentrations cause increased calcium uptake into the sarcoplasmic reticulum (SR) via the SERCA2 transporter. Raised calcium stores in the SR allow for greater calcium release on stimulation, so the myocyte can achieve faster and more powerful contraction by cross-bridge cycling. The refractory period of the AV node is increased, so cardiac glycosides also function to regulate heart rate.

Binding of cardiac glycoside to Na-K ATPase is slow, and after binding, intracellular calcium increases gradually. Thus, the action of digitalis (even on IV injection) is delayed.

Raised extracellular potassium decreases binding of cardiac glycoside to Na-K ATPase. As a consequence, increased toxicity of these drugs is observed in the presence of hypokalemia.

If SR calcium stores become too high, some ions are released spontaneously through SR ryanodine receptors. This effect leads initially to bigeminy: regular ectopic beats following each ventricular contraction. If higher glycoside doses are given, rhythm is lost and ventricular tachycardia ensues, followed by fibrillation.

Examples

Examples of plants producing cardiac glycosides:

Cardenolide type:
- Lily of the Valley (Convallaria majalis)
- Antiaris toxicaria
- Strophanthus – ouabain g/k/e-strophanthin
- Digitalis lanata and Digitalis purpurea – digoxin, digitoxin
- Nerium oleander - oleandrin
- Asclepias sp.
- Calotropis gigantea^[2]
Bufadienolide type:
- Drimia maritima
- Kalanchoe daigremontiana and other Kalanchoe species – daigremontianin and others

References

^ Singh, B. and Rastogi, R.P. 1970. Cardenolides-glycosides and genins. Phytochemistry 9: 315-331.
^ Wang, Z. N.; Wang, M. Y.; Mei, W. L.; Han, Z.; Dai, H. F. (2008). "A New Cytotoxic Pregnanone from Calotropis gigantea". Molecules 13 (12): 3033–9. doi:10.3390/molecules13123033. PMID 19052526.

"Digoxin, oral.". RelayHealth. Retrieved 7 May 2012.

"The Electrophysiological Effects of Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and in Guinea Pig Isolated Hearts.". Cell Physiol Biochem. Retrieved 7 May 2012.

External links

VCU School of Pharmacy Cardiac Glycosides

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. ジギタリス（強心配糖体）中毒 digitalis cardiac glycoside poisoning
2. 収縮能障害による心不全におけるジゴキシンの使用 use of digoxin in heart failure due to systolic dysfunction
3. ジゴキシン中毒患者におけるジゴキシン特異的抗体（Fab）フラグメントに対する投与レジメン dosing regimen for digoxin specific antibody fab fragments in patients with digoxin toxicity
4. ジゴキシンによる治療：初回投与、モニタリング、および用量変更 treatment with digoxin initial dosing monitoring and dose modification
5. ジゴキシン中毒による不整脈 cardiac arrhythmias due to digoxin toxicity

English Journal

Identification and stress-induced expression of three 3β-hydroxysteroid dehydrogenases from Erysimum crepidifolium Rchb. and their putative role in cardenolide biosynthesis.

Munkert J1, Ernst M1, Müller-Uri F1, Kreis W2.Author information 1Pharmaceutical Biology, Department Biology, Friedrich-Alexander University Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany.2Pharmaceutical Biology, Department Biology, Friedrich-Alexander University Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany; ECROPS Erlangen Center of Plant Science, Germany. Electronic address: wolfgang.kreis@fau.de.Abstract3β-Hydroxysteroid dehydrogenases (3βHSD) are supposed to be involved in cardenolide biosynthesis in plants. Erysimum crepidifolium Rchb., a member of the Brassicaceae accumulating cardenolides, is a close relative to Arabidopsis thaliana. Full length cDNAs encoding for three individual 3βHSDs (EcHSD1, EcHSD2, EcHSD3) were isolated from E. crepidifolium leaves. EcHSD1 and EcHSD2 encode proteins assembled from 257 amino acids whereas EcHSD3 encodes a protein assembled from 260 amino acids. All three proteins qualify as members of the short-chain dehydrogenases/reductases family of proteins (SDRs). EcHSD1 and EcHSD2 shared a high amino acid sequence identity of about 86% and 91% with putative 3βHSDs of A. thaliana (AT2G47140 and AT2G47130). EcHSD3 showed high homology to the A. thaliana SDRs AT2G47150 (74%) and AT2G47120 (81%). All three EcHSD genes were expressed in Escherichia coli and the recombinant enzymes were characterized biochemically. All three recombinant EcHSDs catalyzed the dehydrogenation of pregnenolone and the 3-reduction of 5α/β-pregnane-3,20-dione when NAD and NADH were used as cosubstrates, respectively. After exposure to different stress conditions, no increased transcription was seen for EcHSD1 whereas EcHSD2 was expressed four times higher under osmotic stress than under control conditions. EcHSD3 expression was 10 times and 6 times higher after osmotic stress and MeJA treatment, respectively, than in controls.
Phytochemistry.Phytochemistry.2014 Apr;100:26-33. doi: 10.1016/j.phytochem.2014.01.006. Epub 2014 Feb 7.
3β-Hydroxysteroid dehydrogenases (3βHSD) are supposed to be involved in cardenolide biosynthesis in plants. Erysimum crepidifolium Rchb., a member of the Brassicaceae accumulating cardenolides, is a close relative to Arabidopsis thaliana. Full length cDNAs encoding for three individual 3βHSDs (Ec
PMID 24512841

Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation.

Pongrakhananon V1, Stueckle TA2, Wang HY3, O'Doherty GA3, Dinu CZ4, Chanvorachote P5, Rojanasakul Y6.Author information 1Cell-Based Drug and Health Product Development Research Unit, Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, United States.2Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, United States; Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, United States.3Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, United States.4Department of Chemical Engineering, West Virginia University, Morgantown, WV 26506, United States.5Cell-Based Drug and Health Product Development Research Unit, Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.6Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, United States; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, United States. Electronic address: yrojan@hsc.wvu.edu.AbstractAdvanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50=11.9nM) than digitoxin (IC50=90.7nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.
Biochemical pharmacology.Biochem Pharmacol.2014 Mar 1;88(1):23-35. doi: 10.1016/j.bcp.2013.10.027. Epub 2013 Nov 11.
Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its n
PMID 24231508

Bufalin Is a Potent Small-Molecule Inhibitor of the Steroid Receptor Coactivators SRC-3 and SRC-1.

Wang Y1, Lonard DM, Yu Y, Chow DC, Palzkill TG, Wang J, Qi R, Matzuk AJ, Song X, Madoux F, Hodder P, Chase P, Griffin PR, Zhou S, Liao L, Xu J, O'Malley BW.Author information 1Authors' Affiliations: Departments of Molecular and Cellular Biology and Pharmacology, Baylor College of Medicine, Houston, Texas; and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida.AbstractVirtually all transcription factors partner with coactivators that recruit chromatin remodeling factors and interact with the basal transcription machinery. Coactivators have been implicated in cancer cell proliferation, invasion, and metastasis, including the p160 steroid receptor coactivator (SRC) family composed of SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2), and SRC-3 (AIB1/ACTR/NCOA3). Given their broad involvement in many cancers, they represent candidate molecular targets for new chemotherapeutics. Here, we report on the results of a high-throughput screening effort that identified the cardiac glycoside bufalin as a potent small-molecule inhibitor for SRC-3 and SRC-1. Bufalin strongly promoted SRC-3 protein degradation and was able to block cancer cell growth at nanomolar concentrations. When incorporated into a nanoparticle delivery system, bufalin was able to reduce tumor growth in a mouse xenograft model of breast cancer. Our work identifies bufalin as a potentially broad-spectrum small-molecule inhibitor for cancer. Cancer Res; 74(5); 1506-17. ©2014 AACR.
Cancer research.Cancer Res.2014 Mar 1;74(5):1506-17. doi: 10.1158/0008-5472.CAN-13-2939. Epub 2014 Jan 3.
Virtually all transcription factors partner with coactivators that recruit chromatin remodeling factors and interact with the basal transcription machinery. Coactivators have been implicated in cancer cell proliferation, invasion, and metastasis, including the p160 steroid receptor coactivator (SRC)
PMID 24390736

Japanese Journal

Acylated Kaempferol Glycosides from Laurus nobilis Leaves and Their Inhibitory Effects on Na⁺/K⁺-Adenosine Triphosphatase

Lee Sooryun,Chung Soon-Chun,Lee So-Hyoung [他],Park Wanki,Oh Ikhoon,Mar Woongchon,Shin Jongheon,Oh Ki-Bong
Biological and Pharmaceutical Bulletin 35(3), 428-432, 2012
… Na+/K+-adenosine triphosphatase (ATPase) inhibitors have considerable therapeutic potential against some heart diseases like congestive heart failure and cardiac arrhythmias. …
NAID 130001872327

Perfectly regioselective acylation of a cardiac glycoside, digitoxin, via catalytic amplification of the intrinsic reactivity

Yoshida Keisuke,Furuta Takumi,Kawabata Takeo
Tetrahedron Letters 51(37), 4830-4832, 2010-09-15
Organocatalytic regioselective acylation of digitoxin has been developed. This method provides the 4′′′-O-manoacylate as the sole product without the concomitant formation of diacylates. The extremely …
NAID 120002484958

Antiproliferative Activity of Derivatives of Ouabain, Digoxin and Proscillaridin A in Human MCF-7 and MDA-MB-231 Breast Cancer Cells(Pharmacology)

Winnicka Katarzyna,Bielawski Krzysztof,Bielawska Anna [他],SURAZYNSKI Arkadiusz
Biological & pharmaceutical bulletin 31(6), 1131-1140, 2008-06-01
… All these data emphasize the potential usefulness of these derivatives of cardiac glycosides as anticancer agents. …
NAID 110006684329