Helveticoside Exhibited p53-dependent Anticancer Activity Against Colorectal Cancer.

BACKGROUND: Investigation into the anti-cancer activities of natural products and their derivatives represents an efficient approach to develop safe and effective chemotherapeutic agents for the treatment of colorectal cancer. Helveticoside is a biologically active component of the seed extract of Descurainia sophia. This compound has been reported to regulate the genes related to cell proliferation and apoptosis in lung cancer cells, however its anticancer activity has not been fully explored yet. METHODS: Cell viability was evaluated by MTT and Trypan blue exclusion assay; cell apoptosis was measured by flow cytometry; mitochondrial membrane potential was determined by using JC1-mitochondrial membrane potential assay kit; protein levels were determined by western blot assay; in vivo tumor growth was assessed in a xenograft nude mice model. RESULTS: The current study demonstrated the in vitro anti-cancer activity of helveticoside against colorectal cancer using colorectal cancer cells SW480 and HCT116. Moreover, induction of apoptosis was found to mediate the cytotoxic action of helveticoside on SW480 and HCT116 cells. Based on the decrease in the mitochondrial membrane potential, upregulation of Bax, downregulation of Bcl-2 and cleavage of caspase-3 and 9, apoptosis was induced by helveticoside via mitochondria-mediated intrinsic apoptotic signaling pathways in colorectal cancer cells. Besides, using p53-knockout SW480 cells, the cytotoxic action of helveticoside was found to be p53-dependent. More importantly, administration of helveticoside inhibited the growth of HCT116 cells derived-colorectal cancer xenograft in mice via activation of apoptosis. CONCLUSIONS: Helveticoside might be a potential candidate for the development of novel chemotherapeutic agents for the treatment of colorectal cancer, while the potential toxic effects of helveticoside may be worthy of further investigations.

[Tolerance to cardiotoxic effect of strophanthane K in experimental total heart block and electrocardiostimulation]. / Izuchenie tolerantnosti k kardiotoksicheskomu deistviiu strofantina K pri éksperimental'noi polnoi poperechnoi blokade serdtsa i élektrokardiostimuliatsii.

Tolerance to the cardiotoxic effect of strophanthin K was studied in narcotized dogs with experimental complete heart block (CHB) and ventricular electrostimulation. A threshold to the toxic arrhythmogenic effect of strophanthin K was significantly reduced as compared to that in the control group. As the electrocardiostimulation (ECS) frequency increased, the minimum arrhythmogenic dose of strophanthin K showed a growth, while not reaching a level for the sinus rhythm. It is concluded that the basic mechanisms of the arrhythmogenic effect of strophanthin K under the conditions studied are the trigger activity in dogs with ECS and the increased peacemaker's activity in dogs with CHB.

Antioxidants as antiarrhythmic drugs.

Experiments on rats and rabbits using models of arrhythmias induced by vasopressin, epinephrine, strophanthin, and CaCl2 showed that antioxidants derived from 1,4-dihydropyridines, dibunol, and alpha-tocopherol possessed antiarrhythmic effects. Administration of these antioxidants decreased the occurrence of extrasystoles, disturbances of atrioventricular conductivity and ventricular fibrillation. These drugs also prevented changes in membrane phospholipid composition, inhibited activation of peroxidation, decreased phospholipase activity, prevented a decrease of Ca2+ ATPase and Ca2+ binding and uptake by sarcoplasmic reticulum, and increased sarcolemmal Na+, K+-ATPase, sarcoplasmic reticulum creatine phosphokinase.

[Complications after intravenous administration of anti-arrhythmia agents]. / Oslozhneniia pri vnutrivennom vvedenii antiaritmicheskikh preparatov.

The frequency and nature of side-effects are analysed in 945 patients subjected to 1205 intravenous infusions of various antiarrhythmic agents. The most common side-effects of novocainamide, isoptin, obsidan, lidocain and trimecain are arterial hypotension and shock, while conductivity disorders, asystole (novocainamide, isoptin), bradycardia, acute heart failure (obsidan) are less frequent. Rapid strophanthin saturation in patients with supraventricular paroxysmal tachyarrhythmias can result in ventricular extrasystole, and the use of phenylephrine hydrochloride can produce an excessive hypertensive response. The occurrence of side-effects can be reduced considerably if antiarrhythmic agents are employed on a correct methodological basis, with adequate infusion rate observed, the first dose correctly chosen, potassium preparations added to the treatment, etc.

[Biochemical markers of strophanthin arrhythmia]. / Biokhimichsckie predvestniki strofantinovoi aritmii.

The increase of the concentration of fatty acids, the reduction in the concentration of serotonin, the lowering of the activity of glucose-6-phosphate dehydrogenase and transketolase, and the development of compensated metabolic acidosis were discovered in the stage that preceded strophanthine arrhythmia. These characteristics may be recommended for a wider use on the clinical basis for predicting arrhythmias in the treatment of cardiac glycosides.

[Role of inflammation mediators in the etiology of hypersensitivity to strophanthin in various experimental heart diseases]. / Uchastie mediatorov vospaleniia v geneze giperchuvstvitel'nosti k strofantinu pri nekotorykh vidakh éksperimental'noi patologii serdtsa.

Effects of histamine and serotonin on strophanthine cardiotoxicity were examined in experiments on 312 cats. It was shown that inflammation mediators exert sympathomimetic action on the myocardium and potentiate strophanthine cardiotoxicity. These effects can be prevented by premedication with the beta-blocker alprenolol, antihistaminic, steroid and non-steroidal anti-inflammatory agents. It was disclosed that premedication with diphenhydramine, analgin and hydrocortisone might correct strophanthine tolerance decreased as a result of coronary artery occlusion. The conclusion is made that inflammation mediators play a role in the genesis of strophanthine hypersensitivity in experimental myocardial infarction.

[Effect of strophanthin and cytochrome C on myocardial contraction and the incidence of shock and ventricular fibrillation in experimental myocardial infarct]. / Vliianie strofantina i tsitokhroma C na sokratitel'nuiu funktsiiu miokarda, chastotu shoka i fibrilliatsii zheludochkov pri eksperimental'nom infarkte miokarda.

High ligation of the interventricular artery caused ventricular fibrillation in the first 2--4 minutes in 20% of cats. In the remaining animals myocardial contractility diminished to half its initial value. After that, contractility increased gradually. In cardiosclerosis myocardial contractility reduced by 20--30%. Ligation of the interventricular artery on the background of cardiosclerosis induced cardiogenic shock in half of the animals. Cytochrome C does not reduce the diminution of myocardial contractility after ligation and has a marked antifibrillatory effect. Strophantin does not affect the diminution of contractility of a healthy myocardium but reduces the decrease in contractility of a sclerosed myocardium and also promotes the development of ventricular fibrillation following ligation of the interventricular artery.

Deleterious synergism of a cardiac glycoside and sodium diatrizoate.

Studies were performed in mice to determine if the cardiac glycoside, Strophanthin-K, and the contrast medium, sodium diatrizoate, interact synergistically to produce death. Intravenous injections of lethal and near lethal doses of the two agents produced a significantly greater mortality than the individual agents alone. Low or near clinical doses of Strophanthin-K, when given with doses of diatrizoate in the lethal range, produced mortalities significantly greater than did the diatrizoate alone. Similarly, low or near clinical doses of diatrizoate given with doses of Strophanthin-K in the lethal range produced mortalities significantly greater than for the Strophanthin-K alone. Isotonic or hypertonic saline, when substituted for diatrizoate or Strophanthin-K did not produce synergistic increases in mortality. Thus neither the injection volume, nor agent hypertonicity or ionic strength, seem to be the primary factors in the synergism to produce death. The diatrizoate anion appears to be an important factor. Until more information is available from other animal models it appears that patients receiving cardiac glycoside should be considered to have a higher than normal risk of serious reactions to contrast media in intravenous urography.

[Effect of cardiac desympathization, stimulation of the central adrenergic structures and blockade of beta-adrenergic receptors on cardiotonic and cardiotoxic effect of cardiac glycosides]. / Vliianie desimpatizatsii serdtsa, razdrazheniia tsentral'nykh adrenergicheskikh struktur i blokady beta-adrenergicheskikh retseptorov na kardiotonicheskoe i kardiotoksicheskoe deistvie serdechnykh glikozidov.

The object of study were rabbits who had been subjected to ligation of 3 or 4 large branches of the left descending coronary artery 14-20 days before the experiment. In experiments with surgical desympathization of the heart it was established that the inotropic effect of cardiac glycosides did not depend on the concentration of catecholamines in the myocardium. In stimulation of adrenergic structures of the posterior hypothalamus attended with an increase in sympathetic innervation of the cardiovascular system the cardiotoxic threshold of cardiac glycosides was considerably reduced. Propranolol (Inderal) administered in a dose which blocks the beta-adrenergic apparatus of the heart prevents the development of the positive inotropic effect of therapeutic doses of strophanthin K on a hypodynamic left ventricular myocardium.

["Digitalis" arrhythmias and their treatment]. / "Digitalisnye" aritmii i ikh lechenie

The observation was conducted in 92 patients with rhythm and conductivity disorders induced by cardiac glycosides. Most of the patients had ischaemic heart disease, 60 of them having had acute myocardial infarction. All patients were prescribed cardiac glycosides (usually Strophantin and digitalis preparations) due to the appearance of cardiac insufficiency. The most frequently observed rhythm disorder consisted in ventricular extrasystole (69.5% of the cases), bigeminy, polytopic or group extrasystole being observed in many cases. Often arrhythmias consisted in atrial extrasystole, atrial fibrillation, atrial and ventricular tachycardia, atrioventricular block. "Digitalis" arrhythmias were treated with beta-adrenergic blockers: Inderal, Viskene, Eraldin, Trasicor and Aptin. These drugs proved effective in most cases with atrial arrhythmias and in some--with ventricular arrhythmias. Lidocain was more effective in cases of ventricular arrhythmias. Effective drugs of a broad spectrum are also Aimalin, Pulsenorma and Ritmodan.