Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylase inhibitor (HDAI) induces accumulation of highly acetylated histones by inhibiting the activity of histone deacetylase and inhibits cell proliferation, induces differentiation, and promotes apoptosis. TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis in various human cancer cells, a promising observation because it raises the possibility of a death ligand selectively for tumor cells. However, resistance to TRAIL-induced apoptosis was seen in colonic adenocarcinoma cell lines. So we investigated whether human colonic adenocarcinoma cell lines can be sensitized to TRAIL-induced apoptosis by the addition of HDAI. We investigated sensitivity to histone deacetylase inhibitor in colonic adenocarcinoma cell lines using the MTT assay. Cell viability decreased with sodium butyrate (SB) and trichostatinA (TSA) in a dose-dependent manner in LS 180 and HT-29 cells. Nuclear condensation and fragmentation were observed by DAPI staining after 24 h stimulation with SB or TSA in LS 180 cells. We also investigated the combination of HDAI and TNF family members (TRAIL, anti-Fas antibody or TNFalpha) in colonic adenocarcinoma cell lines. HDAI augmented TNF family-related apoptosis in LS 180 cells and HT-29 cells. HDAI sensitizes human colonic adenocarcinoma cell lines to TRAIL-mediated apoptosis. HDAI may be useful as an adjuvant agent for TRAIL in the treatment of human colonic adenocarcinomas that are resistant to TRAIL.
Int J Mol Med 2002 May
PMID:Histone deacetylase inhibitors sensitize human colonic adenocarcinoma cell lines to TNF-related apoptosis inducing ligand-mediated apoptosis. 1195 60

The process of apoptosis is responsible for normal cellular turnover in numerous tissues throughout the body. The endometrial layer of the uterus shows steroid-dependent cyclic changes in structure and function. After a proliferative and secretory phase, steroid support is withdrawn and the uterine epithelium is shed. We hypothesize that the apoptosis observed in endometrial cells following hormonal withdrawal is mediated by the Fas/Fas ligand (FasL) system. Normal endometrial cells and endometrial cancer cells were cultured in the presence of estrogen and progesterone. In order to mimic physiological hormonal changes, estrogen and progesterone were removed from the media. Apoptosis was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-dephenyl tetrazolium bromide (MTT) assay and propidium iodide staining, while Fas and FasL expression were evaluated by Western blot analysis. The endometrial cells expressed Fas and low levels of FasL. Withdrawal of estrogen and/or progesterone from the culture induced apoptosis causing an approximately 50% decrease in cell viability. This coincided with increased Fas and FasL expression. Treatment of the cells with anti-FasL antibody prevented cell death following hormonal withdrawal. Estrogen and progesterone therefore represent survival factors which hamper cell death by impeding the expression of apoptotic factors. Our results indicate that Fas-mediated apoptosis is important for endometrial cycling and suggest that dysregulation of the Fas/FasL interactions may have an important role in the development of endometrial cancer.
Mol Hum Reprod 2002 May
PMID:Hormonal regulation of apoptosis and the Fas and Fas ligand system in human endometrial cells. 1199 42

There is considerable interest among basic and clinical researchers in novel drugs with activity against leukemia. The vast history of experience of traditional Chinese medicine (TCM) with medicinal plants may facilitate the identification of novel antileukemic compounds. In the present investigation, we tested 22 drugs for their activity toward CCRF-CEM cell lines: artesunate, artemisinin, baicalein, baicalin, berberine, bufalin, cantharidin, cephalotaxine, curcumin, daidzein, daidzin, diallyl disulfide, ginsenoside Rh2, glycyrrhizic acid, isonardosinon, homoharringtonine, nardosinon, nardofuran, puerarin, quercetin, tannic acid, and tetrahydronardosinon. As compounds from folk medicinal remedies are sometimes looked upon as alternative medicine with some hesitation or criticism, we investigated only chemically pure compounds and tested the drugs independently in two different laboratories in Germany and Australia. We used CCRF-CEM parental cells and doxorubicin-selected P-glycoprotein (P-gp)/MDR1-expressing CEM/ADR5000, vinblastine-selected P-gp/MDR1-expressing CEM/VLB(100), and epirubicin-selected multidrug resistance-related protein 1 (MRP1)-expressing CEM/E1000 sublines thereof. While CEM/ADR5000, CEM/VLB(100), and CEM/E1000 cells were highly resistant to the corresponding selecting agents, no or only minimal degrees of cross-resistance were observed to TCM drugs in both growth inhibition assay and MTT assay (range from 0.4- to 8-fold). Homoharringtonine, artesunate, and bufalin were most active among this panel of compounds. As shown by flow cytometry, artesunate significantly increased daunorubicin accumulation in CEM/E1000 cells, but not in CEM/VLB(100) or CCRF-CEM parental cells. Bufalin caused a small, but significant increase in daunorubicin accumulation in CEM/VLB(100) and CEM/E1000 cells. As artesunate and bufalin showed both antileukemic activity if applied alone and modulation activity in combination with daunorubicin in multidrug-resistant (MDR) cells, these two drugs may be suitable for novel combination treatment regimens to improve leukemia cell killing.
Blood Cells Mol Dis
PMID:Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells. 1206 12

Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As(2)O(3) might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As(2)O(3) to induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3) was determined to be 10 microM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 microM As(2)O(3) for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 microM As(2)O(3) by a Western blot analysis. Next, we examined the MAP kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells. As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell death. These results suggest that As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.
J Biochem Mol Biol 2002 Jul 31
PMID:Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. 1229 96

1. Morphologically developmental properties of fetal mouse cortical neurons in the chemically defined serum- and antioxidant-free culture condition were observed. Also, cellular composition in cultures was identified by immunostaining with anti-NSE and anti-GFAP. 2. Various cell densities ranging from 1 x 10(3) to 1 x 10(6) cells/cm2 were prepared to further assess the effect of cell density on time-course of neuronal survival by counting the number of remaining attached neurons after 3 and 7 days in culture. 3. Neuronal responses to neurotrophic effect of NGF on neurite outgrowth and neuroprotective effect of MK-801 against glutamate-induced excitotoxity were evaluated by image analysis and MTT assay, respectively. 4. Results showed that this culture system was neuronal-enriched with a neuronal lifetime more than 35 days. Neurons survived best when seeded at a density > or =1.5 x 10(5) cells/cm2. Cultured neurons were capable of exhibiting sensitive responses to the effects of NGF and MK-801. 5. These findings suggest that this primary culture system provides a sensitive and powerful in vitro model for pharmacological screen and studies of neurotrophic and neuroprotective agents.
Cell Mol Neurobiol 2002 Apr
PMID:A serum- and antioxidant-free primary culture model of mouse cortical neurons for pharmacological screen and studies of neurotrophic and neuroprotective agents. 1236 2

We investigated the relationship between the antiproliferative effect of GnRH agonist and telomerase activity using the endometrial cancer cell line HEC-1A. The subjects were 38 endometrial cancer, and 2 atypical endometrial hyperplasia patients. GnRH-R expression was detected using RT-PCR. HEC-1A cells were incubated with 10(-7)-10(-4) M GnRH agonist (leuprolide acetate), and cell proliferation was determined using MTT assay. The telomerase activity was detected by the TRAP assay and expression of human telomerase reverse transcriptase (hTERT) was assessed by RT-PCR. GnRH-R mRNA was detected at 94.7% (36/38) in endometrial cancer and in both of the atypical endometrial hyperplasia and in HEC-1A cells. Cell proliferation of HEC-1A showed significant inhibition at leuprolide acetate concentrations of 10(-6) M or higher compared with untreated control culture (p<0.05). The telomerase activity showed no marked difference compared with untreated culture. However, hTERT mRNA expression showed a decrease in the leuprolide-treated cells. It is suggested that the mechanism of the antitumor effect of GnRH agonist involved the inhibition of hTERT mRNA expression in the endometrial cancer cells.
Int J Mol Med 2002 Nov
PMID:GnRH agonist inhibits human telomerase reverse transcriptase mRNA expression in endometrial cancer cells. 1237 98

Amyloid beta-peptide (Abeta) effectively inhibits the cellular reduction activity of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in a variety of cultured cells. Although the inhibitory activity is widely used for the estimation of the biological activity of Abeta, the cellular mechanism is unclear. In the present study, we examined the effect of Abeta on the morphology of early endosomes, in which MTT is accumulated as MTT formazan after cellular reduction. We found that Abeta1-40 alters the distribution of Rab5- and early endosomal auto-antigen 1-positive early endosomes in the presence of MTT in HeLa cells, which are susceptible to the Abeta1-40-induced inhibition of cellular MTT reduction. To obtain a clue to the molecular mechanism, we determined whether Abeta1-40 affects the signal cascade of the phosphatidylinositol-3-OH kinase (PI-3K) pathway that is involved in early endosomal trafficking. MTT induced phosphorylation of Akt and mitogen-activated protein kinase. Abeta1-40 suppressed the PI-3K-dependent Akt phosphorylation but not the mitogen-activated protein kinase phosphorylation. Thus, Abeta seems to modulate early endosomal trafficking via inhibition of the PI-3K pathway in the presence of MTT. Modulation of early endosomal trafficking appears to affect the cellular metabolism of MTT, causing suppression of cellular MTT reduction by Abeta. These findings may help clarify the mechanism of the cytotoxicity of Abeta.
Brain Res Mol Brain Res 2002 Oct 15
PMID:Amyloid beta-peptide alters the distribution of early endosomes and inhibits phosphorylation of Akt in the presence of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). 1239 69

Phosphatidic acid, the main product of lipid breakdown through phospholipase D activation, has been implicated in important signal transduction pathways able to influence cell fate in many ways. The purpose of this work was to determine possible effects of phosphatidic acid on neuronal cell death pathways. Here we used cerebellar granular cell cultures and cell death was triggered with either staurosporine or H(2)O(2). Cell viability was quantified by spectrophotometry, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) test. Staurosporine (1-3 microM) or H(2)O(2) (50-800 microM) induced cell death in a dose-dependent manner. Using fluorescent staining (propidium iodide or annexin V-Cy3/6-carboxyfluorescein) we showed that cell death was mostly apoptotic in staurosporine treated cells and mostly non-apoptotic (necrotic) in H(2)O(2) treated cells. Phosphatidic acid was able to increase cell viability in staurosporine-, but not in H(2)O(2) - treated cells. We therefore conclude that phosphatidic acid has neuroprotective potential in neurons exposed to stimuli that trigger apoptosis.
J Cell Mol Med
PMID:Selective protection by phosphatidic acid against staurosporine-induced neuronal apoptosis. 1241 61

1. Guanosine-5'-monophosphate (GMP) was evaluated as a neuroprotective agent against the damage observed in rat hippocampal slices submitted to an in vitro model of ischemia with or without the presence of the ionotropic glutamate receptor agonist, Kainic acid (KA). 2. Cellular injury was evaluated by MTT reduction, lactate dehydrogenase(LDH) release assay, and measurement of intracellular ATP levels. 3. In slices submitted to ischemic conditions, 1 mM GMP partially prevented the decrease in cell viability induced by glucose and oxygen deprivation and the addition of KA. 4. KA or N-methyl-D-aspartate (NMDA) receptor antagonists, gamma-D-glutamylamino-methylsulfonate (GAMS) or (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, 20 microM) also prevented toxicity in hippocampal slices under ischemic conditions, respectively. 5. The association of GMP with GAMS or MK-801 did not induce additional protection than that observed with GMP or that classical glutamate receptor antagonists alone. 6. GMP, probably by interacting with ionotropic glutamate receptors, attenuated the damage caused by glucose and oxygen deprivation in hippocampal slices. This neuroprotective action of GMP in this model of excitotoxicity is of outstanding interest in the search for effective therapies against ischemic injury.
Cell Mol Neurobiol 2002 Jun
PMID:Neuroprotective effect of GMP in hippocampal slices submitted to an in vitro model of ischemia. 1246 74

Cyclin D1 is essential for Neu-induced cell growth and is induced by growth factors through Ras-dependent and Ras-independent signaling pathways (1). Because flavopiridol, a novel flavanoid cyclin-cyclin-dependent kinase inhibitor, may function through Ras-dependent and/or -independent pathways, we hypothesized that treatment of breast cancer cells with inhibitors of Neu signaling and flavopiridol might synergize to inhibit proliferation. Human breast cancer cell lines, which express high levels of endogenous Neu receptor, were treated with the anti-Neu antibody, trastuzumab, together with flavopiridol and subject to MTT assay. Cell lines were assayed for alterations in cell cycle by fluorescence-activated cell sorter and signaling proteins by Western blot. Flavopiridol and trastuzumab synergistically inhibited DNA synthesis, cellular proliferation, and contact-dependent growth. Cytotoxic synergy was observed independent of the sequence of addition of the two drugs to cultured cells. In SKBR3 cells, a combination of trastuzumab and flavopiridol inhibited the Ras-MAPK-Akt pathway, decreased cyclin D1 abundance, and kinase activity to a greater extent than either drug alone. Compared with single-agent treatment, combination treatment selectively inhibited Akt and pRB phosphorylation. Cytotoxic synergy was observed with flavopiridol plus LY294002 (selective phosphatidylinositol 3-kinase inhibitor) but not with PD98059 (selective mitogen-activated protein kinase kinase 1 inhibitor) suggesting that Akt inhibition may be important in synergy. Zinc-induced overexpression of cyclin D1 in T-47D deltaMTcycD1 cells were more resistant to drug-induced cell death when compared with vector-transfected T-47D deltaMT cells. Cyclin D1 overexpression reverses drug treatment induced cell cycle arrest in SKBR3 cells. Flavopiridol and trastuzumab yield cytotoxic synergy in human breast cancer cells overexpressing Neu. Cyclin D1 overexpression results in combination drug resistance. In addition, inhibition of Akt may prove to be a useful therapeutic strategy in combination with flavopiridol.
Mol Cancer Ther 2002 Jul
PMID:Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways. 1247 66


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