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)

2-Methoxyestradiol (2-MeOE2) treatment caused significant growth inhibition of H460 and A549 human lung cancer cell lines which contain wild-type p53. However, 2-MeOE2 had a little effect on the p53 negative H358 and p53 mutated H322 cell lines. Western blot analysis indicated that 2-MeOE2 treatment resulted in an eightfold increase in the endogenous wild-type p53 protein, while the level of the mutant p53 protein remained unchanged. TdT staining indicated that following 2-MeOE2-mediated increases in wildtype p53 protein, cells bypass the G1-S checkpoint of the cell cycle with 30 to 40% undergoing apoptosis. Introduction of anti-sense wt-p53 into wt-p53 cells abrogated the 2-MeOE2 effect. A significant portion of lung cancer retains the wild-type p53 gene therefore, 2-MeOE2 may have therapeutic application.
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PMID:Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. 901 25

2-Methoxyestradiol (2-ME) is a physiological metabolite of estrogen, which is excreted with the urine. In contrast to most estrogens, tumor growth-inhibiting effects were observed. Further studies have revealed that it may be an effective anticancer compound for many tumor types. Several different mechanisms have been attributed to 2-ME. Besides a strong antiangiogenic effect on endothelial cells and tumors, there is a tubulin-inhibiting mechanism, causing cells to arrest in the G2/ M phase of the cell cycle. In other tumors, p53-dependent and p53-independent mechanisms with induction of apoptosis have been shown. The number of different tumors examined for a growth-inhibiting effect is increasing, and new mechanisms are continuously described. In vivo studies in mice, rats, and dogs show no or very little toxicity, even at high doses. Here, we discuss the antitumor activity and their mechanisms. 2-ME appears to be a new anti-tumor compound with strong potential for clinical application.
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PMID:The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors. 1146 76

2-Methoxyestradiol (2-ME), an endogenous metabolite of 17beta-estradiol, is present in human blood and urine. Here we show for the first time that 2-ME significantly inhibited the growth of normal prostate epithelial cells and androgen-dependent LNCaP and androgen-independent DU145 prostate cancer cells. This growth inhibition was accompanied by a twofold increase in the G(2)/M population, with a concomitant decrease in the G(1) population, as shown by cell-cycle analysis. 2-ME treatment affected the cell-cycle progression of prostate cancer cells specifically by blocking cells in the G(2) phase. Immunoblot analysis of the key cell-cycle regulatory proteins in the G(2)/M phase showed a 14-fold increase in the expression of p21 and an eightfold increase in the expression of p34 cell division cycle 2 (cdc2). We also found an accumulation of phosphorylated cdc2 after 2-ME treatment. Furthermore, Wee 1 kinase was detectable after 2-ME treatment. 2-ME treatment also led to an increase in the activity of caspase-3, followed by apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick end-labeling and fluorescein isothiocyanate-poly(ADP-ribose) polymerase assay. Estrogen receptor levels did not change after treatment with 2-ME. Examination of the signaling pathways that mediate 2-ME-induced apoptosis showed reduction in the level of p53 expression and its DNA-binding activity. Given the fact that p53 mutations are common in patients with metastatic prostate cancer, our finding that 2-ME-mediated growth inhibition of human prostate cancer cells occurred in a p53-independent manner has considerable clinical significance. These findings, combined with the limited toxicity of 2-ME, may have significant implications for alternative treatment of advanced prostate cancer.
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PMID:2-methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells. 1147 20

2-Methoxyestradiol (2ME), a metabolite of estradiol (E), inhibits proliferation of various tumor cells. In this study we determined the effect of 2ME on human glioblastoma cell lines, in vitro. We compared these cells with cultured astrocytes obtained from traumatized adult rat striatum. Exposure to 2ME had a strong antiproliferative effect on human glioblastoma and caused an increase in the population of apoptotic cells, detected by flow cytometry, in some of the investigated cell lines. A significant number of cells were blocked in the G2/M phase of the cell cycle. Concurrently, the population of cells in the G1 phase decreased in all glioblastoma cell lines. Staining with Hoechst 33258 revealed abnormal nuclear morphology in the proliferating cells treated with 2ME. Treatment with 2ME induced upregulation of wild type p53 in one of the human glioblastoma cell lines as well as in proliferating adult rat astrocytes. We conclude that 2ME inhibits the growth of human glioblastoma cell lines and induces apoptosis, in vitro. This compound deserves further investigation as a treatment for gliomas.
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PMID:2-Methoxyestradiol inhibits proliferation of normal and neoplastic glial cells, and induces cell death, in vitro. 1531 84

2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with promise for cancer chemotherapy, including advanced prostate cancer. We have focused on events related to cell cycle arrest (G1 and G2/M) and induction of apoptosis in human prostate cancer cells. Treatment with 2-ME increased cyclin B1 protein and its associated kinase activity followed by later inhibition of cyclin A-dependent kinase activity and induction of apoptosis. Similar results were obtained with paclitaxel (taxol), a clinically relevant agent used to treat advanced prostate cancer. Cyclin-dependent kinase inhibitors prevented 2-ME and paclitaxel-mediated increase in cyclin B1-dependent kinase activity and blocked induction of apoptosis. Reduction of X-linked inhibitor of apoptosis (XIAP) protein by 2-ME and paclitaxel correlated with increased apoptosis. Lower doses of 2-ME and paclitaxel resulted in G1 (but not G2/M) cell cycle arrest in the p53 wild type LNCaP cell line, but with minimal induction of apoptosis. We suggest that 2-ME and paclitaxel-mediated induction of apoptosis in prostate cancer cells requires activation of cyclin B1-dependent kinase that arrests cells in G2/M and subsequently leads to the induction of apoptotic cell death.
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PMID:2-Methoxyestradiol and paclitaxel have similar effects on the cell cycle and induction of apoptosis in prostate cancer cells. 1635 31

2-Methoxyestradiol (2ME) is an endogenous metabolite with estrogen receptor-independent anti-tumor activity. The current study seeks to determine the mechanism of anti-tumor activity of 2ME on human chondrosarcoma. 2ME caused a time- and dose-dependent cytotoxity in chondrosarcoma cells, while primary chondrocytes were minimally affected. Cells accumulated in G0/G1 phase in response to 2ME and DAPI stain indicated an induction of apoptosis. Bax, Cytochrome C, and Caspase-3 protein expression were increased, while p53 expression was decreased. A higher Bax/Bcl-2 ratio followed 2ME treatment. 2ME has a potentially promising role as a systemic therapy of chondrosarcoma when the mechanism of action is better delineated.
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PMID:2-methoxyestradiol induces apoptosis and cell cycle arrest in human chondrosarcoma cells. 1741 81

2-Methoxyestradiol (2ME), a natural derivative of estradiol, is currently evaluated in clinical trials for breast cancer. The current study aims to evaluate the modulatory effects of 2ME on regulation of multidrug resistance (MDR) in doxorubicin (Dox) resistant breast cancer cells (MCF-7/Dox) and its underlying mechanisms. The chemosensitizing effect of 2ME on Dox cytotoxicity is tested by MTT assay. RT(2) Profiler PCR Array was used to identify differentially expressed genes in Dox and/or 2ME treatment groups, based on significance of results 4 genes were selected: MDR1, Bcl2, P53 and Cyclin D1. The expression of these genes was confirmed using western blotting. Lastly, functions of these genes were examined by studying p-glycoprotein (p-gp) function, caspase 3 activity and flowcytometric cell cycle assays respectively. 2ME significantly increased sensitivity of the resistant MCF-7/Dox cells to the cytotoxic effect of Dox by 2.9-folds. The array and western blotting showed that Bcl2 and Cyclin D1 expression were down regulated; P53 expression was not affected while MDR1 was over expressed by combination of 2ME with Dox. 2ME increased p-gp function by 24+/-7.05%, compared to control. Addition of 2ME to Dox increased caspase activity by 27-folds. Combination of 2ME to Dox arrested the cell cycle in G(1) and S phases, compared to Dox. In conclusion, 2ME chemosensitizes resistant breast cancer cells to Dox cytotoxicity by down regulating expression of Bcl2 and Cyclin D1, augmenting caspase 3 activity as well as inducing cell cycle block in G(1) and S phases.
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PMID:2-Methoxyestradiol and multidrug resistance: can 2-methoxyestradiol chemosensitize resistant breast cancer cells? 1822 36

2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17beta-Estradiol (E2), induces cell death in osteosarcoma cells. To further understand the molecular mechanisms of action, we have investigated cell cycle progression in 2-ME-treated human osteosarcoma (MG63, SaOS-2 and LM7 [corrected]) cells. At 5 microM, 2-ME induced growth arrest by inducing a block in cell cycle; 2-ME-treatment resulted in 2-fold increases in G1 phase cells and a decrease in S phase cells in MG63 and SaOS-2 osteosarcoma cell lines, compared to the appropriate vehicle controls. 2-ME-treatment induced a threefold increase in the G2 phase in LM7 [corrected] osteosarcoma cells. The results demonstrated steroid specificity, as the tumorigenic metabolite, 16alpha-hydroxyestradiol (16-OHE), did not have any effect on cell cycle progression in osteosarcoma cells. The cell cycle arrest coincided with an increase in expression of the cell cycle markers p21, p27 and p53 proteins in 2-ME-treated osteosarcoma cells. Also, MG63 cells, transiently transfected with cDNA for a 'loss of function mutant' RNA-dependent protein kinase (PKR) protein, were resistant to 2-ME-induced cell cycle arrest. These results suggest that 2-ME works in concert with factors regulating cell cycle progression, and cell cycle arrest precedes cell death in 2-ME-treated osteosarcoma cells.
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PMID:2-methoxyestradiol-induced cell death in osteosarcoma cells is preceded by cell cycle arrest. 1838 13

2-Methoxyestradiol (2-ME2) is an endogenous metabolite of 17beta-estradiol (E2) with estrogen receptor-independent anti-cancer activity. The current study sought to determine the mechanism of anti-cancer activity of 2-ME2 in human acute T lymphoblastic leukemia CEM cells. Results showed that 2-ME2 markedly suppressed proliferation of CEM cells in a time- and dose-dependent manner. 2-ME2-treated CEM cells underwent typical apoptotic changes. Exposure to 2-ME2 led to G(2)/M phase cell-cycle arrest, which preceded apoptosis characterized by the appearance of a sub-G(1) cell population. In addition, cytosolic cytochrome c release, increased procaspase-9 and -3 expressions, poly(ADP-ribose) polymerase (PARP) cleavage, and induced expression of caspase-8 were detected, suggesting that both the intrinsic apoptotic pathway and extrinsic apoptotic pathway were involved in 2-ME2-induced apoptosis. Moreover, the expression level of p21 protein was upregulated, whereas Bcl-2 and dysfunctional p53 protein were downregulated, which also contributed to 2-ME2-induced apoptosis. Our findings revealed that 2-ME2 might be a potent natural candidate for chemotherapeutic treatment of human acute T lymphoblastic leukemia when the precise effects of 2-ME2 were investigated further in other T leukemia cell lines and in primary T-cell leukemias.
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PMID:2-Methoxyestradiol blocks cell-cycle progression at the G2/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells. 2073 53