Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein tyrosine kinase inhibitor, genistein, has been reported to inhibit proliferation and to induce cell death in various non-solid and solid cancer cell lines. Herein, we examined the effects of genistein in several human malignant glioma cell lines. We found that genistein inhibited the proliferation of LN-18, LNT-229, LN-308 and T98G cells at EC50 concentrations of 25-80 microM (72 h of exposure). The growth of a non-neoplastic immortalized human astrocyte cell line, SV-FHAS, was inhibited at similar concentrations. There was a reduction in [3H]-methylthymidine incorporation and a moderate lactate dehydrogenase release as a sign of cell death in genistein-treated glioma cells. Electron microscopy showed morphological changes with mitochondrial swelling and apoptosis in glioma cells treated with high concentrations of genistein. Genistein-induced cytotoxicity was associated with an increased DNA/topoisomerase II complex formation. Furthermore, genistein induced cell cycle arrest in G2/M. There was an increase in the p53 and p21 levels in response to genistein. However, there was no difference in genistein sensitivity between p21-deficient colon carcinoma cells and isogenic control cells. Genistein-induced cell death in LN-18 and LNT-229 was unaffected by the ectopic expression of the preferential caspase 1/8 inhibitor, crm-A, or co-exposure to the pan-specific pseudosubstrate caspase inhibitor, zVAD-fmk. The ectopic expression of the anti-apoptotic BCL-2 protein attenuated the cytotoxic effects of genistein. Moreover, the ectopic expression of temperature-sensitive p53V135A, which acts as a dominant-negative p53 mutant at 38.5 degrees C but assumes p53 wild-type properties at 32.5 degrees C, in LN-18 or LNT-229 cells, had no effect on genistein cytotoxicity at either temperature. Genistein did not act in synergy with CD95 ligand-induced apoptosis or various cancer chemotherapy drugs in cytotoxic or clonogenic cell death assays. Thus, genistein-like protein kinase inhibitors are promising agents for the experimental treatment of malignant gliomas.
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PMID:The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines. 1835 97

5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a phylogenetically conserved serine/threonine protein kinase. AMPK may inhibit cell growth and proliferation and also regulates apoptosis. 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a cell-permeable AMPK activator. Activation of AMPK with AICAR has been shown to induce apoptosis of the rat hepatoma cell line FTO2B cells and almost completely inhibited HepG2 cells growth. In this study, a HepG2 cell line, which was transfected with a vector containing human CYP2E1 cDNA (E47 cells), was treated with AICAR. Cell proliferation was blocked, and apoptosis and necrosis were elevated as assessed by cellular morphology, DNA content assay, and lactate dehydrogenase leakage. AICAR treatment significantly increases CYP2E1 activity (20-fold) and expression (5.5-fold) in E47 cells. Iodotubericidin, which inhibits the conversion of AICAR to its activated form AICAR monophosphate, the antioxidants trolox and MnTMPyP, and 4-methylpyrazole, an inhibitor of CYP2E1, all can protect the E47 cells from AICAR-induced necrosis. Production of intracellular reactive oxygen species was increased by AICAR treatment in E47 cells. The cytotoxicity mechanism of AICAR in E47 cells is suggested to include AMPK activation, p53 phosphorylation, p21 expression, overexpression of CYP2E1, and intracellular ROS accumulation.
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PMID:Overexpression of CYP2E1 induces HepG2 cells death by the AMP kinase activator 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). 1847 82

Okadaic acid (OA) is a polyether fatty acid produced mainly by dinoflagellates causing diarrhoeic shellfish poisoning (DSP) in humans. To resolve the controversies concerning its genotoxicity in vitro, we have investigated eventual specific cellular response in DOK, Caco-2 (Deltap53/p53(-)), HepG-2 and C6 glioma cells using the DNA damage detection test (3d DNA repair test: nucleotide excision repair (NER) and base excision repair (BER)), caspase-3-triggered apoptosis, neutral red (NR) and lactate dehydrogenase (LDH) release tests. At low concentrations of OA (10nM), cytotoxicity measured by LDH release is more marked in DOK cells, indicating necrotic cell death that occurs only slightly in HepG-2 cells. At the same concentration, caspase-3 activation-dependent apoptosis and DNA damage caused by OA were only detected in HepG-2 cells. This apoptosis appears to be p53 gene dependent. Cell death occurs in the other cell types only by necrosis at OA concentrations amended to cultures. Among the tested cell lines, HepG-2 cells are the most sensitive to OA (10-50nM) at 12 and 72h as revealed by the NR test. The 3D test shows that only HepG-2 cells bear damaged DNA at tested concentrations. It is concluded that the genotoxicity of OA is chiefly cell type dependent and concentration dependent, giving sense to controversial genotoxicity data found in the literature.
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PMID:The cytotoxicity and genotoxicity of okadaic acid are cell-line dependent. 1853 64

Oridonin, a diterpenoid isolated from Rabdosia rubescences, has been reported to have antitumor effects. In this study, the growth-inhibitory activity of oridonin for L929 cells was exerted in a time-and dose-dependent manner. After treatment with oridonin for 24 h, L929 cells underwent both apoptosis and necrosis as measured by an lactate dehydrogenase (LDH) activity-based assay. A rapid generation of reactive oxygen species (ROS) was triggered by oridonin, and subsequently up-regulation of phospho-p53 (ser 15) expression and an increased expression ratio of Bax/Bcl-2 was observed. Furthermore, there was a significant fall in mitochondrial membrane potential (MMP) and increase in caspase-3 activity after exposure to oridonin for 24 h. Surprisingly, the pan-caspase inhibitor z-VAD-fmk and caspase3 inhibitor z-DEVD-fmk rendered L929 cells more sensitive to oridonin, rather than preventing oridonin-induced cell death. Oridonin and z-VAD-fmk co-treatment not only resulted in an even higher ROS production, but also made a more significant reduction in the MMP. Pretreatment of ROS scavenger N-acetylcysteine (NAC) led to a complete inhibition of oridonin-induced cell death, intracellular ROS generation, and MMP collapse. NAC treatment also reversed the potentiation of cell death by the pan-caspase inhibitor z-VAD-fmk. Taken together, these observations showed that oridonin-induced cell death in L929 cells involved intracellular ROS generation, activation of phospho-p53 (ser 15), and up-regulation of the Bax/Bcl-2 ratio; and the augmented cell death by z-VAD-fmk was dependent on an increased ROS production.
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PMID:Caspase inhibition augmented oridonin-induced cell death in murine fibrosarcoma l929 by enhancing reactive oxygen species generation. 1881 79

Excessive UVR ranks among the most harmful environmental influences on human skin. However, the direct impact of UVR on human skin appendages remains to be systematically investigated. Organ-cultured human anagen hair follicles in vitro were irradiated, and reduction of hair shaft elongation, premature catagen entry, and reduced hair matrix keratinocyte proliferation were observed upon irradiation with UVB (20/50 mJ cm(-2)). At 20 mJ cm(-2), apoptotic cell death prevailed (casp-3/p53 activation), whereas at 50 mJ cm(-2), necrotic cell death was predominant (lactate dehydrogenase increase). Mitochondrial common deletion and oxidatively damaged genomic DNA (8-OH-dG) was mainly observed at 20 mJ cm(-2). Follicular melanogenesis and ACTH immunoreactivity drastically declined, but alpha-melanocyte-stimulating hormone remained unchanged, whereas transforming growth factor-beta(2) expression shifted from the outer toward the inner root sheath. Both the number of Giemsa+ mast cells and the degree of mast-cell degranulation increased in the connective tissue sheath (CTS), and CD117 immunoreactivity of CTS cells and matrix keratinocytes was upregulated. Thus, UVR differentially modifies hair growth and cycle, promotes cell death, and induces complex regulatory events in human hair follicles in vitro. The leads from this human organ model, which is a living and human tissue interaction system under physiologically relevant in situ conditions, may encourage its use for general investigation of UV-induced effects as well as for testing possible agents for their UV-protective potency.
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PMID:Profiling the response of human hair follicles to ultraviolet radiation. 1915 39

The objective of this study was to investigate the chemopreventive potentials of glycine- and proline-rich glycoprotein (SNL glycoprotein, 150-kDa) isolated from Solanum nigrum Linne on formation of colonic aberrant crypt foci (ACF) induced by 1,2-dimethylhydrazine (DMH, 20 mg/kg) in A/J mice. Administration of SNL glycoprotein inhibited phosphorylation of extracellular signal-regulated kinase (ERK), expression of colonic proliferating cell nuclear antigen (PCNA), and frequency of colonic ACF in DMH-stimulated mice colon carcinogenesis. In addition, SNL glycoprotein increased expression of cyclin-dependent kinase inhibitors (p21(WAF/Cip1) and p27(Kip1)), whereas reduced expression of precursor form of apoptosis-related proteins [pro-caspase-3 and pro-poly(ADP-ribose)polymerase (PARP)] in the mice. Interestingly, the results in this study revealed that SNL glycoprotein has suppressive effects on activity of nuclear factor-kappa B (NF-kappaB), whereas it has stimulatory effect on the expression of p53, accompanying inhibitory effects on expression of NF-kappaBp50, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha in DMH-stimulated ACF formation. Also, SNL glycoprotein has inhibitory effects on the formation of thiobarbituric acid reactive substances (TBARS), on the production of inducible nitric oxide (NO), and on the release of lactate dehydrogenase (LDH) in the mice plasma. Collectively, our findings in this study suggest that SNL glycoprotein has chemopreventive activity via modulation of cell proliferation and apoptosis in DMH-treated A/J mice.
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PMID:Glycine- and proline-rich glycoprotein regulates the balance between cell proliferation and apoptosis for ACF formation in 1,2-dimethylhydrazine-treated A/J mice. 1918 65

This study was aimed to investigate the significance of interphase fluorescence in situ hybridization (FISH) in detecting +12, del (13q14), p53 and atm gene deletion in chronic lymphocytic leukemia (CLL). FISH and a panel of probes (CEP 12, LSI D13S319, LSI p53, LSI atm) were used to detect molecular cytogenetic abnormalities in 30 patients with CLL. Cytogenetic aberrations and their relation with some other prognostic factors (peripheral lymphocyte count, Binet stage, LDH level, ZAP-70 and so on) were analyzed. The results indicated that out of the 30 CLL patients, molecular cytogenetic aberrations were found in 19 (63.3%) cases and 7 (23.3%) patients showed more than two kinds of abnormalities. The most frequent abnormality detected was del (13q14) (43.3%), followed by trisomy of chromosome 12 (23.3%), del (atm) (13.3%) and del (p53) (10.0%). There were no significant differences between molecular cytogenetic aberrations and sex, age, Binet stage, peripheral lymphocyte count, or the serum levels of lactate dehydrogenase (LDH), beta(2)-microglobulin (beta(2)-MG), or ZAP-70. The incidence of atm gene deletion was higher in the group of CD38 high expression than that in the group of low expression (p = 0.035). It is concluded that FISH is a rapid and sensitive technique in analysing molecular cytogenetic abnormalities, but its prognostic significance in CLL needs to further investigate.
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PMID:[Detection of molecular cytogenetic abnormalities in 30 patients with chronic lymphocytic leukemia by fluorescence in situ hybridization]. 1923 42

The aim of the present paper was to investigate the synergistic effect and mechanism of anticancer activity of Zuojinwan ( ZJW) comprising Coptis chinensis Franch ( HL) and Evodia rutaecarpa (Juss.) Benth ( WZY) at a ratio of 6 : 1 (w/w). In vivo anticancer activity testing was carried out by inhibiting the growth of S180 tumor. Tumor growth inhibition, spleen index, lymphocyte proliferation, apoptosis, tumor necrosis factor-alpha (TNF-alpha) level, activities of serum tumor markers (TMs), increase in life span (ILS), histopathology and gene expression were tested. The results indicated that ZJW could significantly induce apoptosis of cancer cells. The inhibition ratio, ILS and TNF-alpha levels of mice treated with ZJW were 50.54 %, 64.91 % and 1.04 ng/mL, respectively, much higher than HL and WZY when singly used. Furthermore, the activities of acid phosphatase and alkaline phosphatase were significantly increased and the activities of creatine kinase, aldolase and lactate dehydrogenase were reduced in serum, and the expressions of Bax and wild-type p53 proteins were much higher for the mice treated by ZJW compared with HL and WZY single-treatment groups. A clear synergistic effect on the anticancer activity was observed with ZJW, and the mechanism of antitumor growth may be due to an effect on gene expression and activities of tumor markers in serum.
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PMID:In vivo inhibition of S180 tumors by the synergistic effect of the Chinese medicinal herbs Coptis chinensis and Evodia rutaecarpa. 1935 Apr 78

Nematode infections cause human morbidity and enormous economic loss in livestock. Since resistance against currently available anthelmintics is a worldwide problem, there is a continuous need for new compounds. The cyclooctadepsipeptide PF1022A is a novel anthelmintic that binds to the latrophilin-like transmembrane receptor important for pharyngeal pumping in nematodes. Furthermore, PF1022A binds to GABA receptors, which might contribute to the anthelmintic effect. Like other cyclodepsipeptides, PF1022A acts as an ionophore. However, no correlation between ionophoric activity and anthelmintic properties was found. This is the first study describing the effect of PF1022A on mammalian cells and tissues. While channel-forming activity was observed already at very low concentrations, changes in intracellular ion concentrations and reduction of contractility in isolated guinea pig ileum occurred at multiples of anthelmintically active concentrations. PF1022A did not induce necrotic cell death indicated by complete lack of cellular lactate dehydrogenase release. In contrast, apoptosis induction via the mitochondrial pathway was suggested for long-term drug treatment at high concentrations due to numerous apoptotic morphological changes as well as mitochondrial membrane depolarisation. Short time effects were based on cell cycle blockade in G(0)/G(1) phase. Additionally, the cell cycle and apoptosis regulating proteins p53, p21 and bax, but not Bcl-2 were shown to impact on PF1022A-induced cytotoxicity. However, since PF1022A-induced cytotoxicity was found at drug concentrations higher than those used in anthelmintic treatment, it can be suggested that PF1022A intake might not impair human or animal health. Thus, PF1022A seems to be a safe alternative to other anthelmintic drugs.
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PMID:Effects of the anthelmintic drug PF1022A on mammalian tissue and cells. 1942 83

This study was to clarify whether acrylamide (ACR) will induce apoptosis and astrogliosis in an astrocytic cell line in vitro. Different time- and dose-dependent cytotoxic studies were conducted upon neuronal (SH-SY5Y) and glial cell lines (U-1240 MG) under exposure to ACR up to 72h. We showed that SH-SY5Y cells were more sensitive in cytotoxic assays than U-1240 MG cells, and significantly decreased cell viability was observed at concentrations higher than 1mM with increased lactate dehydrogenase leakage observed only at 5 and 10mM in U-1240 MG cells. The ACR-induced apoptotic responses and phosphorylation of p53 protein at Ser15 for U-1240 MG cells were identified at 48h. The increase of glial fibrillary acidic protein (GFAP) as a chemical-induced astrogliotic response was found to be associated with different ACR concentrations and exposure times, particularly at >or=48h of >or=2mM. In addition, immunocytochemical staining at 36h of 5 and 10mM treatments had significantly higher density of GFAP than the control. Thus, ACR-induced effects can be seen in neuronal and astrocytic cells. These results suggest that ACR exposure may lead to apoptotic and astrogliotic effects in human astrocytoma cells in vitro in a time- and dose-dependent manner.
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PMID:Acrylamide-induced astrogliotic and apoptotic responses in human astrocytoma cells. 1942 97


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