Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone is a tissue that responds to mechanical load by changing its internal architecture. However, the mode of transmission of mechanical stimuli into biological signals and the effect of load at the cellular level are still not clear. An in vitro system, a Flexercell Strain Unit, was used to apply cyclic load to osteoblast-like cells in culture. In the first series of experiments, ROS 17/2.8 rat osteosarcoma cells, cultured on Flex I, flexible bottomed culture plates, were subjected to a 0.05 Hz, 0.24 STRAIN cyclic load regime for 3 and 7 days, in vitro. One group subjected to load received verapamil, a calcium channel blocker, throughout the experimental period. A second group was exposed to load but received no verapamil. A third group had no drug or load and a fourth group had no load but received verapamil. Cultures were incubated for 24 hours prior to collection with 10 microCi of 45CaCl in the medium, then well bottoms were divided to yield outer (maximum) and inner (minimum) load zones for assay of radioactivity. The effect of verapamil during a 7-day loading period was studied by adding the drug to individual cultures at daily intervals. Results indicated that mechanical loading stimulates calcium incorporation in ROS 17/2.8 cell cultures by day 7 but not by day 3. Only early verapamil addition decreased load-induced calcium incorporation when drug was added prior to day 4. If verapamil was added after 4 days, the channel blocker did not diminish load-induced calcium incorporation.
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PMID:Verapamil decreases cyclic load-induced calcium incorporation in ROS 17/2.8 osteosarcoma cell cultures. 128 12

Injections of parathyroid hormone (PTH) result in increased bone formation in several species. Work in our laboratory and others has shown a stimulation of bone cell proliferation and growth factor production by PTH. Our purpose was to study the effects of PTH on a human bone cell line using TE-85 human osteosarcoma cells as a model. After 24 h treatment, PTH caused an increase in cell proliferation as measured by cell counts and [3H]-thymidine incorporation. Proliferation was not inhibited by an anti-transforming growth factor beta (TGF beta) antibody which could abolish stimulation by exogenous TGF beta. PTH did not stimulate cAMP production, alkaline phosphatase activity or production of insulin-like growth factors I or II (IGF-I or IGF-II) in TE-85 cells. Although basal TE-85 proliferation was slowed by incubation with the calcium channel blocking agent verapamil, PTH still caused an increase in growth rate. We conclude that PTH directly stimulates TE-85 proliferation via a mechanism not involving increased adenylate cyclase activity or increased secretion of IGF-I, IGF-II or TGF beta and may stimulate bone formation in vivo by activating some other mitogenic signal to increase bone cell proliferation.
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PMID:PTH stimulates the proliferation of TE-85 human osteosarcoma cells by a mechanism not involving either increased cAMP or increased secretion of IGF-I, IGF-II or TGF beta. 131 2

UMR 106 rat osteogenic sarcoma cells were studied with the whole cell patch clamp technique to investigate the presence of voltage-gated inward currents. In barium (Ba2+)-containing medium, depolarizing jumps revealed both transient (T-type) and sustained (L-type) Ba2+ currents. The L-type component was dihydropyridine-sensitive: the agonist Bay K 8644 increased the amplitude of the L-type Ba2+ current. A new dihydropyridine calcium channel blocker, S 11568 ((+/-)-2(2-[2-(aminoethoxy)ethoxyl]methyl)4-(2',3'- dichlorophenyl)3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4- dihydropyridine, and its enantiomers, S 12967 ((+)-S 11568) and S 12968 ((-)-S 11568), inhibited the L-type Ba2+ current. IC50 values at a holding potential (VH) of -50 mV were 90 nM for S 11568, 800 nM for S 12967 and 45 nM for S 12968. At VH = -80 mV, S 12968 was less potent (IC50 near 500 nM). In contrast, S 12968 was without appreciable effect on the T-type component of the inward current through Ca2+ channels. Our results indicate that UMR 106 cells express both T-type and L-type Ca2+ channels and could be used to study the modulation by Ca2+ channel blocking agents, such as S 12968, of the hormonal regulation of Ca2+ fluxes across the osteoblast membrane.
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PMID:Ca2+ channel inhibition in a rat osteoblast-like cell line, UMR 106, by a new dihydropyridine derivative, S11568. 138 78

A variety of tumors stimulate platelet activation. Because platelet activation may, in part, require calcium channel mobilization, we evaluated whether calcium channel blocking agents inhibit osteogenic sarcoma induced platelet aggregation. Platelet rich plasma (PRP) from normal subjects was incubated with one of four calcium channel-blocking agents: nifedipine, diltiazem, verapamil, or amlodopine, all 0-25 micrograms/ml, or diluent. Osteogenic sarcoma cells (2 or 4 x 10(6)/ml) were then added. Platelet aggregation was monitored by light transmission through PRP, and residual PRP was processed for electron microscopy. MG63 cells caused aggregation of PRP in most subjects (mean, 36 +/- 3%). Calcium channel-blocking agents (nifedipine greater than diltiazem greater than amlodopine greater than verapamil) caused partial inhibition of osteogenic sarcoma-induced platelet aggregation, at high concentrations only. Electron microscopy showed platelets aggregating to each other and to tumor cell membranes within 1-5 minutes. Changes in pattern of platelet clumping around tumor cells occurred when PRP was incubated with high concentration of diltiazem (50 micrograms). This study shows that calcium channel-blocking agents inhibit osteogenic sarcoma-induced platelet aggregation when used in high doses.
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PMID:Effects of calcium channel-blocking agents on platelet-osteogenic sarcoma interaction: platelet aggregation and electron microscopic findings. 238 1

An osteoblast calcium channel demonstrated by single channel recordings is associated with calcium antagonist receptor binding sites in osteoblast-like osteosarcoma cells. By using whole cell current recordings we now show that this channel is stimulated by the dihydropyridine calcium agonist drug BAY K 8644. A physiological relevance of these channels is apparent from the stereoselective, potent inhibition of parathyroid hormone-stimulated calcium uptake into osteoblast-like cells in culture by desmethoxyverapamil, a phenylalkylamine calcium antagonist. Secretion by these cells of the bone matrix protein osteocalcin is stimulated by BAY K 8644 and blocked by desmethoxyverapamil and nitrendipine. Evidence for a role of this channel in bone remodeling in intact animals comes from enhanced bone resorption in fetal rat bones observed with BAY K 8644 and stereoselective, potent blockade of resorption by desmethoxyverapamil.
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PMID:Bone remodeling signaled by a dihydropyridine- and phenylalkylamine-sensitive calcium channel. 246 65

A slowly inactivating inward calcium current was identified in the rat osteosarcoma cell line ROS 17/2.8 using a combination of ion flux and electrophysiological techniques. Voltage dependence, dihydropyridine sensitivity, divalent cation selectivity, and single channel properties identified this current as a high threshold, "L-type" calcium current. Ion flux experiments using 45Ca2+ confirmed that calcium uptake through these channel represents a major pathway for calcium entry into osteosarcoma cells. In resting cells, i.e. at negative membrane potentials, stimulation of both calcium current and rapid 45Ca2+ influx could be elicited by concentrations of 1,25-(OH)2-vitamin D3 between 0.1 and 3 nM. At these concentrations, 1,25-(OH)2-vitamin D3 shifted the threshold for activation of inward calcium current to more negative potentials. At higher concentrations (5-10 nM), inhibitory effects became predominant. These opposing effects are functionally similar to those of the dihydropyridine BAY K 8644. Other vitamin D3 metabolites (25-(OH)-D3 and 24,25-(OH)2-D3) exhibited less potent stimulatory effects and greater inhibition of calcium current than 1,25-(OH)2-D3. These results suggest that (i) vitamin D3 acts as a potent modulator of calcium channel function in osteosarcoma cells, and (ii) intracellular Ca2+-dependent signaling processes may be affected acutely by physiological concentrations of vitamin D3 metabolites.
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PMID:Vitamin D3 metabolites modulate dihydropyridine-sensitive calcium currents in clonal rat osteosarcoma cells. 247 47

The role of cAMP and calcium in the induction of ornithine decarboxylase (ODC, E.C.4.1.1.17) activity in the osteogenic sarcoma cell line, UMR 106-01, was studied, with particular interest for parathyroid hormone (PTH). PTH and forskolin dose-dependently induced the ODC activity and the cAMP production. Protein synthesis is involved in the effect of PTH and forskolin on ODC activity but not on cAMP production. Using quin2 we showed that 20 nM PTH and 10 microM forskolin increased the intracellular ionized calcium concentration ([Ca2+]i), thereby offering the possibility for calcium to play a role as cellular mediator in the action of PTH and forskolin in bone. Data obtained with A23187 showed that solely an increase of the [Ca2+]i is not sufficient to stimulate basal or potentiate PTH- and forskolin-induced ODC activity. However, the effects of calcium channel blockers and EGTA on basal and PTH- and forskolin-induced ODC activity point to a specific role for calcium. Moreover, the effects of calcium channel blockers and EGTA on basal and PTH- and forskolin-induced cAMP production indicate that the involvement of calcium in the induction of ODC activity is primarily located at another site than the adenylate cyclase. These data indicate that calcium is involved in the control of basal ODC activity. Furthermore, these data suggest that both cAMP and calcium are involved in the induction of ODC activity by PTH and forskolin. More precisely, ODC activity in UMR 106-01 cells can be induced by PTH and forskolin via a calcium-dependent cAMP messenger system.
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PMID:Involvement of cAMP and calcium in the induction of ornithine decarboxylase activity in an osteoblast cell line. 284 Apr 35

The present study evaluates in osteosarcoma cells, the effects of a calcium channel inhibitor nicardipine in 24-hydroxylase activity and 45Ca desaturation curve in presence of 1,25-dihydroxycholecalciferol (1,25(OH)2D3). This sterol induced an increase in 24-OHase activity and 45Ca fluxes. Nicardipine reversed the effect of 1,25(OH)2D3 on 45Ca fluxes but reinforced the enhancement of the 24-OHase activity. The fact that the effects of 1,25(OH)2D3 were reduced by cycloheximide support the hypothesis of a de novo protein synthesis. Our study has allowed us to dissociate the effects of 1,25(OH)2D3 on 24-OHase enhancement from those on Ca2+ transport.
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PMID:Calcium-transport in quiescent and 1,25-dihydroxycholecalciferol-stimulated human osteosarcoma cells. Role in 24 hydroxylase enhancement. 316 48

Suspensions of living human fibroblast induce fibrin clot retractile activity (FCR). The efficiency is dependent on the growth phase; it is maximal during active growth and reduced in post-confluent cultures. In contrast human osteosarcoma cells constantly exhibit very low FCR efficiency. Two different calcium channel-blocking drugs Diltiazem and Verapamil inhibit, depending on the concentrations employed, FCR, and spreading within the clots of the normal cells. Intermediate FCR levels are associated with intermediate degrees of spreading. A similar dose dependent inhibition is also obtained by treating the normal cells with the calmodulin inhibitor trifluoperazine (TFP). On the other hand, treatment of the normal cells with the monoclonal antibody ALB6 which is directed at the human leukocyte differentiation antigen CD9 (p24) causes a significant increase in the FCR efficiency in post-confluent normal cells, but it has no effect on the Te85 osteosarcoma cells. Moreover ALB6 IgG reverses the FCR inhibitory effect of the calcium-channel blocking drugs but not that of TFP. This means that the ALB6 IgG target on the cellular membrane is probably the same as that of the two drugs and that ALB6 IgG is active in the regulation of the calcium flux which controls fibrin clot retractile activity of normal human fibroblasts.
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PMID:Modulation of fibroblast-induced clot retraction by calcium channel blocking drugs and the monoclonal antibody ALB6. 386 83

Osteoblasts express calcium channels that are thought to be involved in the transduction of extracellular signals regulating bone metabolism. The molecular identity of the pore-forming subunit (alpha 1) of L-type calcium channel(s) was determined in rat osteosarcoma UMR-106 cells, which express an osteoblast phenotype. A homology-based reverse transcriptase-polymerase chain reaction cloning strategy was employed that used primers spanning the fourth domain. Three types of cDNAs were isolated, corresponding to the alpha 1S (skeletal), alpha 1C (cardiac), and alpha 1D (neuroendocrine) isoforms. In the transmembrane segment IVS3 and the extracellular loop formed by the IVS3-S4 linker, a single pattern of mRNA splicing was found that occurs in all three types of calcium channel transcripts. Northern blot analysis revealed an 8.6-kb mRNA that hybridized to the alpha 1C probe and 4.8- and 11.7-kb mRNAs that hybridized to the alpha 1S and alpha 1D probes. Antisense oligonucleotides directed to the calcium channel alpha 1D transcript, but not those directed to alpha 1S or alpha 1C transcripts, inhibited the rise of intracellular calcium induced by parathyroid hormone. However, alpha 1D antisense oligonucleotides had no effect on the accumulation of cAMP induced by parathyroid hormone. When L-type calcium channels were activated with Bay K 8644, antisense oligonucleotides to each of the three isoforms partially inhibited the rise of intracellular calcium. The present results provide evidence for the expression of three distinct calcium channel alpha 1-subunit isoforms in an osteoblast-like cell line. We conclude that the alpha 1D isoform is selectively activated by parathyroid hormone.
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PMID:Multiple calcium channel transcripts in rat osteosarcoma cells: selective activation of alpha 1D isoform by parathyroid hormone. 747 9


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