Fusaric acid inhibits proliferation and induces apoptosis through triggering endoplasmic reticulum stress in MCF-7 human breast cancer cells.

Breast cancer has replaced lung cancer to be the leading cancer in the world. Currently, chemotherapy is still the major method for breast cancer therapy, but its overall effect remains unsatisfactory. Fusaric acid (FSA), a mycotoxin derived from fusarium species, has shown potency against the proliferation of several types of cancer cells, but its effect on breast cancer cells has not been examined. Therefore, we explored the possible effect of FSA on the proliferation of MCF-7 human breast cancer cells and uncovered the underlying mechanism in the present study. Our results showed that FSA has a strong anti-proliferative effect on MCF-7 cells through inducing ROS production, apoptosis and arresting cell cycle at G2/M transition phase. Additionally, FSA triggers endoplasmic reticulum (ER) stress in the cells. Notably, the cell cycle arrest and apoptosis inducing effect of FSA can be attenuated by ER stress inhibitor, tauroursodeoxycholic acid. Our study provide evidence that FSA is a potent proliferation inhibition and apoptosis inducing agent against human breast cancer cells, and the possible mechanism involves the activation of ER stress signaling pathways. Our study may highlight that FSA is promising for the future in vivo study and development of potential agent for breast cancer therapy.

Fusaric acid: a novel agent and mechanism to treat HNSCC.

OBJECTIVE: A new class of carboxylic acids has tumoricidal activity for head and neck squamous cell cancer (HNSCC). Fusaric acid (FA) can chelate divalent cations, especially zinc, and inactivate zinc finger proteins involved in DNA repair and protein synthesis. METHODS: 2 squamous carcinoma lines were utilized for in vitro and in vivo portions of this study. Cell counting and flow cytometry were used to analyze cells in culture in treatment and control groups over 96 hours. HNSCC subcutaneous implants were created in treatment and control groups of BALB-c nude mice (N = 30). RESULTS: In vitro studies demonstrated significant changes in cell numbers and cell cycle. In vivo studies of daily intralesional therapy for 1 month also showed reduced onset of growth and overall growth compared to controls. CONCLUSION: FA appears to have a tumoristatic/tumoricidal effect on HNSCC. Further nude mice studies are needed to optimize dosing and administration regimens for FA in anticipation of clinical trials.

[Comparative effectiveness of the beta-(N,N-diethylamino)ethylamide hydrochloride of fusaric acid, obzidan and atenolol in experimental adrenaline-induced cardiac arrhythmia]. / Sravnitel'naia éffektivnost' gidrokhlorida beta-(N,N-diétilamino)étilamida fuzarinovoi kisloty, obzidana i atenolola pri éksperimental'noi adrenalinovoi aritmii serdtsa.

Hydrochloride beta-(N,N-diethylamino)ethylamide of fusaric acid (DAEA) exerted an antiarrhythmic activity in adrenaline-induced arrhythmia in rats. DAEA single pretreatment in doses of 1-5 mg/kg prevented the disorders of rhythm and conductivity in most animals. A pronounced antiarrhythmic effect was manifest at doses of 2 and 4 mg/kg of DAEA. The comparison of efficacy of DAEA, obzidan and atenolol showed that atenolol exhibited only a low antiarrhythmic activity, DAEA prevented the development of arrhythmia in 50% of animals in a dose of 1.7 mg/kg (1/42 of LD50) and obzidan--1 mg/kg (1/40 of LD50), respectively. The antiarrhythmic effect of DAEA was not followed by marked suppression of cardiac conductivity.

Effect of fusaric acid (a dopamine beta-hydroxylase inhibitor) on phaeochromocytoma.

Fusaric acid, an inhibitor of dopamine beta-hydroxylase, which converts dopamine to noradrenaline, lowered the blood pressure and induced a subjective improvement in patients with phaeochromocytoma. These effects may be due either to an impairment of catecholamine biosynthesis or to a direct action on the blood vessels. The use of this drug in the treatment of patients with inoperable malignant phaeochromocytoma or neuroblastoma may improve symptoms and prolong survival.

[Antihypertensive effect of trifluoropentoxypicolinic acid: a pharmacokinetic study].

Two drugs, trifluoropentoxypicolinic acid (TFP) and 5-butoxypicolinic acid, which are composed of a picolinic acid skeleton and an alkoxyl group, were studied to determine characteristics of their antihypertensive effect. The study was carried out using normotensive rats and experimental hypertensive rats (DOCA type hypertensive, one-kidney type hypertensive and spontaneous hypertensive), and effects of these drugs were compared with those of fusaric acid (5-butylpicolinic acid), which is known as a hypotensive agent inhibiting dopamine beta-hydroxylase. The hypotensive effect of the drugs (10, 30 and 100 mg/kg, p.o.) on normotensive rats was weaker than on hypertensive rats. TFP showed a dose-dependent hypotensive effect which was not influenced by reserpine pretreatment. Though TFP showed the same inhibitory effect on serum dopamine beta-hydroxylase as fusaric acid, it had only approximately 0.5 times the inhibitory activity. However, TFP had a hypotensive effect which was 1.4 times stronger than that of fusaric acid. According to pharmacokinetic analysis based on the determination of blood drug concentration, the transfer rate of fusaric acid from the digestive tract to the blood was much higher than TFP by 1.6 X 10(4) times. Moreover, fusaric acid had a 4.5 times greater disappearance rate than TFP. From the above results, first of all, it is supposed that the antihypertensive effect of TFP is related to inhibition of dopamine beta-hydroxylase. In addition, it is suggested that prolonged presence of unchanged TFP in the blood increases its immediate depressive effect on the cardiovascular system, thereby causing a strong hypotensive effect.

Dopamine beta-hydroxylase inhibition in a patient with Wilson's disease and manic symptoms.

The authors studied the effect of dopamine beta-hydroxylase inhibition on the manic symptoms of a 34-year-old man. They found that fusaric acid decreased the patient's manic symptoms and that his symptoms approximately reverted to their previous state when a placebo was reinstituted.

Cerebral arterial spasm. II. Etiology and treatment of experimental cerebral vasospasm.

Delayed cerebral vasospams is caused by excessive accumulation of dopamine-beta-hydroxylase (DBH) and noradrenaline in cerebral vessel walls. This study demonstrates the mechanisms of delayed spasm, particularly the role of red blood cell components, and the successful relief of delayed cerebral vasospasm. Spasmogenic substances which contained a heme component, such as methemoglobin, methemalbumin and catalase enhanced DBH activity in human serum as measured by a one step chemical spectrophotometric assay. The concentration which gave the highest DBH activity caused the maximum constriction of the basilar artery, when the substances were applied topically. Among components of red cells, methemoglobin, methemalbumin, catalase and nicotinamid adenin dinucleotide (NADH) caused constriction of basilar artery in cats, when applied topically, whereas hematin, hemin and bilirubin caused no significant spasm. An oxyhemoglobin solution obtained by mixture with methemoglobin and ascorbic acid produced no significant vascular spasm either. Relief of delayed cerebral vasospasm was obtained with topical application of specific alpha adrenergic blocking drug such as phenoxybenzamine, specific inhibitors of DBH such as fusaric acid, o-phenanthroline and alphaalpha' dipyridyl beta2 adrenergic stimulants such as salbutamol, and a phosphodiesterase inhibitor, ascorbic acid.

Physiologic mechanisms of bupicomide- and hydralazine-induced increase in plasma renin activity in hypertensive patients.

A study was made of the possible mechanisms underlying bupicomide- and hydralazine-induced increase of plasma renin activity. Six patients with mild to moderate hypertension were treated with both bupicomide and hydralazine on separate occasions in random order. Bupicomide lowered mean arterial pressure from 124.2 +/- 3.7 mm Hg (mean +/- SE) to 107.2 +/- 3.9 mm Hg (P less than 0.001). The associated increase in plasma renin activity was 1.27 ng/ml per hour and the increase in heart rate was 16.5 beats/min. Hydralazine reduced mean arterial pressure from 124.2 +/- 3.7 mm Hg to 107.0 +/- 2.0 mm Hg (P less than 0.01). The associated increase in plasma renin activity was 2.20 ng/ml per hour and the increase in heart rate was 22.4 beats/min. Plasma renin activity during bupicomide and hydralazine administration correlated positively with control plasma renin activity (r = 0.98, P less than 0.001). The log of plasma renin activity correlated positively with heart rate (r = 0.51, P less than 0.02) and negatively with mean arterial pressure (r = -0.62, P less than 0.005). We conclude that control plasma renin activity is a major determinant of change in plasma renin activity during administration of bupicomide or hydralazine. Both an increase in sympathetic activity and a decrease in perfusion pressure may contribute to the bupicomide- and hydralazine-induced increase in plasma renin activity, possibly by a baroreceptor-mediated increase in adrenergic tone.

Suppression of elevated serum TSH levels in hypothyroidism by fusaric acid.

The effect of Fusaric acid (FA), a specific inhibitor of dopamine beta-hydroxylase, on humna TSH and thyroid hormone concentration (T4 and T3) was evaluated. Healthy subjects showed no significant changes in serum T3,T4 and TSH concentrations following the administration of FA calcium salt (FA-Ca) or placebo. Similarly, administration of FA-Ca for 4 weeks to hypertensive patients failed to produce significant changes in the serum T4 or T3 Resin Sponge Uptake values, and in the TSH and T3 responses to TRH. In contrast, FA-Ca produced a significant reduction on the high basal serum TSH level in patients with primary hypothyroidism. The mean nadir was 25% and ranged from 6 to 61%. As in the case of L-Dopa, the effect of FA-Ca on serum TSH is most clearly demonstrated in patients with primary hypothyroidism. Alterations in brain amines may directly or indirectly suppress pituitary TSH secretion. The possibility of changes in the peripheral distribution or turnover rate of TSH has not been excluded.

Effect of fusaric acid on tardive dyskinesia and mental state in psychogeriatric patients. A pilot study.

The effect of fusaric acid 150-450 mg daily on tardive dyskinesia and mental state was studied in 15 chronic psychogeriatric patients. The patient's previous drug treatment was maintained unchanged during the experiment. Fusaric acid significantly relieved oro-facial dyskinesia, tremor, and rigidity, and it improved the mental state of the patients (BPRS). Akathisia was exacerbated, but this change was not significant. Akinesia and anxiety were not altered.

The hypotensive effect of fusaric acid: the results of long-term administration of fusaric acid in elderly hypertensive patients.

The hypotensive effect of fusaric acid calcium salt (Calcium salt of 5-butylpicolinic acid) was examined clinically in 10 elderly hypertensive patients by the long-term administration of this agent and the following results were obtained. 1) The means of the systolic and/or diastolic blood pressures of each patient were significantly lower during the first year of the trial period than those during the one year's control period in all patients. 2) The means of the systolic and/or diastolic blood pressures of each patient were significantly lower during the second year of the trial period than those during the one year's control period in whom administration of fusaric acid calcium salt was continued throughout two years. A significant reduction of the systolic blood pressure was observed in 3 out of 6 patients and that of the diastolic blood pressure was observed in 5 out of 6 patients. 3) Comparison was made between the means of the systolic and diastolic blood pressures during the one year's control period and those during the six month's placebo period after two year's administration of fusaric acid calcium salt. During the placebo period, both systolic and diastolic blood pressures showed a tendency of returning to the levels during the control period confirming the hypotensive effect of this agent. 4) Laboratory findings after one year's administration of fusaric acid calcium salt showed no adverse effect of this agent.

The long-term hemodynamic effect of fusaric acid in elderly hypertensive patients.

The hemodynamic effect of fusaric acid calcium salt (calcium salt of 5-butylpicolinic acid), an inhibitor of dopamine beta-hydroxylase, was studied in long-term administration of this agent in 10 elderly hypertensive patients. The hemodynamic items were measured by dye-dilution method before and 3 months, 6 months and one year after administration of fusaric acid calcium salt. The main hemodynamic changes observed were as follows: 1) Heart rate did not show any consistent change. 2) Systolic, diastolic and mean blood pressure decreased. The mean values of these pressures after fusaric acid calcium salt administration were significantly lower than the mean values before administration of this agent. 3) Total peripheral vascular resistance index decreased. The mean values of this index at 3 months, 6 months and one year after fusic acid calcium salt administration were significantly lower than the mean value before administration of this agent. 4) Cardiac index showed various changes throughout administration of fusaric acid calcium salt. The changes in this index might be secondary following the changes in total peripheral vascular resistance index, an inverse correlation being existed between them. 5) Stroke volume index showed almost a similar pattern of change as observed in cardiac index. An inhibitory action of fusaric acid calcium salt on the inotropism of the heart could be hardly found. 6) Plasma volume showed no tangible changes after fusaric acid calcium salt administration throughout one year. It might be concluded that fusaric acid calcium salt elicited the hypotensive response primarily through the reduction of total peripheral vascular resistance index.

Urinary norepinephrine excretion in elderly hypertensive patients during administration of fusaric acid.

The urinary norepinephrine excretion during fusaric acid calcium salt administration was examined in 5 elderly hypertensive patients by double blind cross-over method. The average daily excretion of the last 5 days during fusaric acid calcium salt or placebo administration of 5 weeks' duration was compared in each patient. In 4 patients except for one, the average daily urinary excretion of norephinephrine during fusaric acid calcium salt administration showed an increase, being highly significant (p less than 0.01) statistically, when compared with that during placebo administration, the latter being essentially unchanged. In the one patient, however, the average daily urinary excretion of norepinephrine was significantly higher during placebo administration than that during fusaric acid calcium salt administration. The relationship between the changes in the average daily urinary excretion of norepinephrine and those in blood pressures seemed to be not consistent. The mechanism which brought about an increased norepinephrine excretion in the urine of the hypertensive patients is not obscure at present.

NIH conference. Dopamine- -hydroxylase. Basic and clinical studies.

Dopamine-beta-hydroxylase, the enzyme responsible for conversion of dopamine to norepinephrine, is released along with catecholamines from the adrenal medulla and from sympathetic nerve endings. The properties and mechanisms of the enzyme's action are discussed and its distribution described. Dopamine-beta-hydroxylase is a valuable indicator of exocytosis as a mechanism for neurotransmitter release. The enzyme is present in plasma, but its levels vary widely between individuals. This variation seems to be related more to genetic factors than to sympathetic nerve activity. Abnormally high or low plasma levels are associated with several diseases. However, the relation of these levels to disease pathogenesis rather than to genetic determinants is unclear. Levels of the enzyme are elevated in patients with pheochromocytoma and decline after removal of the tumor. Dopamine-beta-hydroxylase levels seem to be normal in hypertensive patients. Inhibition of dopamine-beta-hydroxylase provides a useful pharmacologic approach to evaluating the role of norepinephrine in psychiatric disorders.

Time-course changes in blood pressure, urinary excretion of norepinephrine and dopamine after administration of fusaric acid in a single dose in elderly hypertensive patients.

Time-course changes in blood pressure, urinary norepinephrine and dopamine excretion after administration in a single dose of fusaric acid calcium salt were examined in 8 elderly hypertensive patients. Eight elderly hypertensive patients served as controls receiving placebo administration in a single dose. The dose of fusaric acid calcium salt ranged from 5.1 mg/Kg to 6.0 mg/Kg. The results obtained are as follows: 1) Both systolic and diastolic blood pressure showed a significant reduction in fusaric acid calcium salt group, the lowest value of systolic blood pressure being observed from 4 to 8 hrs. and that of diastolic blood pressure being observed from 4 to 6 hrs. after administration of this agent, respectively. Systolic blood pressure returned more slowly to the level before fusaric acid calcium salt administration than diatolic blood pressure did. In placebo group, however, no significant reduction of both systolic and diastolic blood pressures was noted. 2) In fusaric acid calcium salt group, norepinephrine excretion in the urine did not show a diurnal change. In placebo group, however, a tendency of diurnal change was noted. These results would suggest that noepinephrine synthesis might be inhibited temporalily by fusaric acid calcijm salt. 3) In fusaric acid calcium salt group, dopamine excretion in the urine did hardly show a diurnal change. In placebo group, however, a fairly evident diurnal change was observed. The interpretation of these results seems to be difficult in the present state of knowledge of the action of fusaric acid calcium salt in humans.