No abstract available.
Mitochondria* ; Staurosporine*

FLT3 gene mutations occurred in approximately 30% of acute myeloid leukemia (AML) patients, which is closely associated with the occurrence, development and poor prognosis of AML. The therapy targeting at FLT3 mutations might be a promising treatment for AML. Midostaurin can inhibit the activities of III receptor tyrosine kinase encoded by FLT3 gene, induce cell cycle arrest and has a apoptotic effect on primitive AML cells of FLT3 -mutant, FLT3 wild-type and the expression of FLT3 mutated receptor. In view of this, the association between FLT3 mutations and AML, and research advances and clinical applications of midostaurin on the treatment of AML especially for FLT3 mutated AML, are reviewed.
Humans ; Leukemia, Myeloid, Acute ; Mutation ; Staurosporine ; analogs & derivatives

[Ca2+]i transients by reverse mode of cardiac Na+/Ca2+ exchanger (NCX1) were recorded in fura-2 loaded BHK cells with stable expression of NCX1. Repeated stimulation of reverse NCX1 produced a long-lasting decrease of Ca2+ transients ('rundown'). Rundown of NCX1 was independent of membrane PIP2 depletion. Although the activation of protein kinase C (PKC) was observed during the Ca2+ transients, neither a selective PKC inhibitor (calphostin C) nor a PKC activator (PMA) changed the degrees of rundown. By comparison, a non-specific PKC inhibitor, staurosporine (STS), reversed rundown in a dose-dependent and reversible manner. The action of STS was unaffected by pretreatment of the cells with calphostin C, PMA, or forskolin. Taken together, the results suggest that the stimulation of reverse NCX1 by STS is independent of PKC and/or PKA inhibition.
Forskolin ; Fura-2 ; Membranes ; Naphthalenes ; Protein Kinase C ; Staurosporine

Calbindin-D28K has been implicated in the regulation of neuronal cell death. Previously, we demonstrated that calbindin-D28K prevents staurosporine (STS)-induced caspase activation and subsequent apoptosis in a neuronal cell line. However, the role of calbindin-D28K in STS-induced activation of calpain and necrotic cell death was not identified. Staurosporine induced the elevation of intracellular calcium after 1 hr of treatment. Overexpression of calbindin-D28K and presence of a calcium chelator, BAPTA, prevented the increase of calcium in STS-treated cells. Cleavage of Bax by calpain was prevented by the overexpressed calbindin-D28K. Permeabilization of the plasma membrane, a factor in necrosis, as well as apoptotic change of the nucleolus induced by STS, was prevented by calbindin-D28K. Thus, our study suggests that calbindin-D28K may exert its protective functions by preventing calpain activation in necrotic cell death, in addition to its effect on the caspase-apoptosis pathway.
Apoptosis ; Calbindin 1* ; Calcium ; Calpain ; Cell Death ; Cell Line ; Cell Membrane ; Membranes* ; Necrosis ; Neurons ; Staurosporine

OBJECTIVE: A major limiting factor in human cancer chemotherapy is toxicity in normal cells and tissues. Our goal was to determine whether normal proliferating cells could be protected from chemotherapeutic agents by taking advantage of the differential drug sensitivity of cell cycle G1 checkpoint in normal and cancer cells. METHODS: Normal peripheral blood mononuclear cells (PBMC) and ovarian cancer cell lines (OVCAR- 3 and SKOV-3) were initially treated with 10 nM of staurosporine for 48 hours. After removal of staurosporine contained media, both PBMC and ovarian cancer cells were treated with 20 nM of paclitaxel for 24 hours. Cells were then allowed to recover in drug-free medium for 4 days. The DNA contents and cell cycle changes were detected by FACScan flow cytometer in the cells harvested whenever the medium was changed. RESULTS: After pretreatment of ovarian cancer cell lines (OVCAR-3 and SKOV-3) with 10 nM of staurosporine followed by treatment with 20 nM of paclitaxel, both OVCAR-3 and SKOV-3 cells were selectively arrested in G2M phase of cell cycle by paclitaxel and they resumed their proliferative cycle to some extents after the drugs were removed and cultured with fresh media. However. pretreatment with 10 nM of staurosporine protected normal circulating PBMC that had been induced to proliferate in vitro with phytohemagglutinin from paclitaxel. Staurosporine-induced arrest of PBMC in G0/G1 phase was reversible, and arrested cells tolerated 10 nM of paclitaxel in culture. CONCLUSION: OVCAR-3 and SKOV-3 cancer cells can be targeted specifically with paclitaxel, following staurosporine-mediated, selective and reversible G0/G1 arrest in PBMC.
Cell Cycle ; Cell Line ; Cytoprotection ; DNA ; Drug Therapy* ; Humans ; Ovarian Neoplasms ; Paclitaxel ; Staurosporine

BACKGROUND: Impairment of relaxing response and augmentation of contractile response to vasoactive substances have been reported in atherosclerotic arteries. These alterations in vascular reactivity are considered as an underlying mechanism for the development of acute vasospasm in atherosclerotic coronary artery. Recently, it has been reported that lysophophatidylcholine (LPC), an oxidative metabolite of low density lipoprotein causes this functional abnormality. However, the precise mechanism of LPC induced change of vascular reactivity is still uncertain. METHOD: In this study, to elucidate the underlying mechanisms of abnormal vascular reactivity in atherosclerotic coronary artery, we examined the effect of LPC on whole cell K+current using patch clamping technique in rabbit coronary smooth muscle cells. RESULTS: Application of LPC(1microM) showed dual effect on whole cell outward current which depends on the magnitude of test potentials. At relatively high depolarizing test potentials (> 10 mV), LPC increased amplitude of outward current which was blocked by Gd3+ not by iberiotoxin (100 nM) and TEA (1 mM). Reversal potential of this Gd3+sensitive, LPC-induced current was -9.7 +/- 0.6 mV. At less depolarizing test potentials (< 10 mV), LPC decreased whole cell K+currents in a dose dependent manner (from 0.01 to 10 microM) in the range of -30 mV to +0 mV. Half maximal inhibition of K+current was 1.509 microM at 0 mV test potential (n =5). Depolarizing holding potential (0 mV) prevented this LPC-induced inhibition of K+current. Steady state activation and inactivation parameters of K+current were significantly shifted to the positive direction by application of LPC (p < 0.01, n =8). Pretreatment of staurosporine (100 nM), a blocker of protein kinase C partially blocked LPC-induced decrease of K+currents. CONCLUSION: LPC-induced inhibition of voltage dependent K+current may explain abnormal vascular reactivity in atherosclerotic coronary artery.
Arteries ; Constriction ; Coronary Vessels ; Lipoproteins ; Lysophosphatidylcholines* ; Muscle, Smooth* ; Myocytes, Smooth Muscle* ; Protein Kinase C ; Staurosporine ; Tea

PURPOSE: In order to determine whether the Tonicity responsive enhancer binding protein (TonEBP) is expressed by hypertonic and hyperosmolar stress, TonEBP expression was investigated in the retinal ganglion cell (RGC) line, RGC-5 cells. METHODS: After RGC-5 cells were cultured by Staurosporine, TonEBP expression was measured with Western immunoblotting analysis and real-time reverse transcription-polymerase chain reaction in 50 mM NaCl, 100 mM mannitol, 50 mM glucose, or 100 mM glucose at 3, 6, 12, and 24 hours after exposure to each environment. RESULTS: In this study, the protein expression of TonEBP was determined to be statistically significantly checked in 50 mM NaCl after 3, and 6 hours, in 100 mM mannitol after 6 hours, and in 100 mM glucose after 3, and 6 hours. TonEBP messenger Ribonucleic acid (mRNA) expression was determined to be statistically significantly checked in 50 mM NaCl after 3 hours, in 100 mM mannitol after 3, and 24 hours, and in 50 mM glucose after 3, and 24 hours. CONCLUSIONS: These results suggested that TonEBP was expressed by hypertonic and hyperosmolar stress at the protein and mRNA levels. Further studies are nedded to determine the role of TonEBP and the mechanism of expression and regulation of TonEBP.
Blotting, Western ; Glucose ; Mannitol ; NFATC Transcription Factors ; Osmotic Pressure ; Retinal Ganglion Cells ; RNA ; RNA, Messenger ; Staurosporine

Authors studied the regulatory mechanism of protein kinase C on the action of acetylcholine in rabbit carotid artery. The arterial rings were myographied isometrically in an isolated organ bath. In this study, acetylcholine relaxed phenylephrine-induced contraction of rabbit carotid artery in the presence of endothelium. In the pretreatment of methylene blue or nitro-L-arginine, the action of acetylchioline was reduced. Pretreatment of phorbol 12-myristate 13-acetate(PMA) attenuated the action of acetylcholine, but PMA did not attenuated it in the presence of staurosporine, suggesting that protein kinase C suppressed the action of acetylcholine. The potency of phorbol ester on the action of acetylcholine was PMA>phorbol 12, 13-dibutyrate(PDBu)>phorbol 12,13-diacetate(PDA), but the direct effect of phorbol on the contraction of arterial rings was PDBu>PMA>PDA. This implied that protein kinase C involved in the contraction of smooth muscle and the attenuation of the action of acetylcholine were different. PMA did not affect on A23187- and sodium nitroprusside-induced vasorelaxation. Acetylcholine increased tissue cGMP contents, which was reduced by PMA. These results suggest that in rabbit carotid artery protein kinase C reduce acetylcholine-stimuated endothelium derived relaxing factor(EDRF) release by affecting membrane receptor, and do not affect on the function of EDRF and cGMP production in the smooth muscle.
Acetylcholine* ; Baths ; Carotid Arteries* ; Endothelium ; Membranes ; Methylene Blue ; Muscle, Smooth ; Protein Kinase C ; Sodium ; Staurosporine ; Vasodilation

The aim of the present study was to investigate the interaction of estradiol-17beta-bovine serum albumin (E2-BSA) and calcitropic hormones, such as parathyroid hormone, calcitonin, and vitamin D, in regulation of Ca2+ uptake in primary cultured renal proximal tubule cells. Statistically significant increase in Ca2+ uptake was found from 2 hours after E2-BSA (10(-9) M) treatment, while estradiol-17beta (10(-9) M) did not affect. Treatment of the cells with E2-BSA (10(-9) M) together with parathyroid hormone (PTH) (10(-8) M), vitamin D (10(-8) M), or calcitonin (10(-8) M) significantly stimulated Ca2+ uptake by 32.50%, 29.30%, or 27.75%, respectively, compared with the control. However, calcitropic hormones did not exhibit any synergistic effect on the E2-BSA-induced stimulation. E2-BSA significantly increased cAMP generation and PKC activity. The stimulatory effect of cotreatment of E2-BSA and PTH or vitamin D was blocked by SQ22536 (an adenylate cyclase inhibitor) and staurosporine (a PKC inhibitor), but the effect of cotreatment of E2-BSA and calcitonin was not blocked. Furthermore, 8-Br-cAMP and TPA (an artificial PKC promoter) increased Ca2+ uptake by 25.51% and 16.47%, respectively, compared with the control. In conclusion, E2-BSA combined with calcitropic hormones regulated Ca2+ uptake partially via cAMP and PKC-dependent mechanisms in renal proximal tubule cells.
Adenylyl Cyclases ; Calcitonin ; Estradiol ; Parathyroid Hormone ; Serum Albumin ; Staurosporine ; Vitamin D

Long-term treatment of cultured bovine adrenal medullary chromaffin (BAMC) cells with arachidonic acid (100 muM), angiotesnin II (100 nM), prostaglandin E2 (PGE2; 10 muM), veratridine (2 muM) or KCl (55 mM) for 24 hrs increased both norepinephrine and epinephrine levels in the supernatant. Pretreatment with staurosporine (10 nM), a protein kinase C (PKC) inhibitor, completely blocked increases of norepinephrine and epinephrine secretion induced by arachidonic acid, angiotensin II, PGE2, veratridine or KCl. In addition, K252a, another PKC inhibitor whose structure is similar to that of staurosporine, effectively attenuated both norepinephrine and epinephrine secretion induced by arachidonic acid. However, K252a did not affect the catecholamine secretion induced by angiotensin II, PGE2, veratridine or KCl. Our results suggest that staurosporine may inhibit long-term catecholamine secretion induced by various secretagogues in a mechanism other than inhibiting PKC signaling. Furthermore, long-term secretion of catecholamines induced by arachidonic acid may be dependent on PKC pathway.
Angiotensin II ; Arachidonic Acid ; Catecholamines* ; Chromaffin Cells* ; Dinoprostone ; Epinephrine ; Norepinephrine ; Protein Kinase C ; Staurosporine* ; Veratridine