Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Methoxyestradiol (2ME2), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME2 inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME2 is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME2 exerts its effects is still uncertain. This study shows that 2ME2 uses the extrinsic pathway for induction of apoptosis. 2ME2 treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME2-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME2 to induce apoptosis. Because 2ME2 administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.
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PMID:2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway. 1254 4

2-Methoxyestradiol (2ME2) is an endogenous metabolite of 17beta-estradiol (E(2)). This study aims to examine the anti-tumour activities of 2ME2 on the poorly differentiated HONE-1 NPC cell line. At the concentration of 1 microM, 2ME2 was found to induce a short-term reversible G2/M cell-cycle arrest. Further 10-fold increase to 10 microM, 2ME2 induced both irreversible G2/M phase cell-cycle arrest and apoptosis. Induction of apoptosis and G2/M cell-cycle arrest was due to oxidative stress as both apoptosis and the proportion of cells arresting at G2/M phase could be reduced by the superoxide dismutase (SOD) mimetic, TEMPO. Induction of apoptosis was accompanied with proteolytic cleavage of caspase-9 and -3, but not caspase-8. Kinetics studies revealed that 2ME2 induced a time-dependent inhibition of extracellular signal-regulated protein kinase (ERK) and an activation of c-jun N-terminal kinases (JNKs). The chemical inhibitor of JNKs, SP600125, was found to reduce 2ME2-induced apoptosis of the HONE-1 cells. Confocal microscopy revealed that the induction of G2/M cell-cycle arrest was associated with the presence of immunoreactivity of p-cdc2 (Tyr15) in the nucleus. The G2/M cell-cycle arrest is also correlated with an increased level of inactive p-cdc25C (Ser216) in 2ME2-treated HONE-1 cells. Results from this study indicate that production of superoxide anions might be involved in 2ME2-induced apoptosis and G2/M cell-cycle arrest of the HONE-1 cells.
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PMID:Mechanisms of 2-methoxyestradiol-induced apoptosis and G2/M cell-cycle arrest of nasopharyngeal carcinoma cells. 1849 2

Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Fibroblasts are the main cellular ingredients in keloid tissue, which has a relatively low apoptosis level. A natural metabolite of estradiol, 2-Methoxyestradiol (2ME2) exerts a pro-apoptotic effect on tumor cells. In this study, the expression levels of key factors in the apoptosis pathway and the expression level of the proliferating cell nuclear antigen (PCNA) were measured to assess the levels of apoptosis and proliferation in both normal skin fibroblasts and keloid fibroblasts. Twelve samples were obtained from 12 patients: 6 keloid patients and 6 non-keloid patients. All 12 of the patients were randomly selected from the Department of Plastic Surgery at Peking Union Medical College Hospital from June 2016 to December 2016. After cell culture, fibroblasts were divided into the following 6 groups: normal skin fibroblasts (S); keloid fibroblasts (K); keloid fibroblasts treated with 2ME2 (2ME2); keloid fibroblasts treated with DMSO (DMSO); keloid fibroblasts treated with the caspase inhibitor Ac-DEVD-CHO (IN); and keloid fibroblasts treated with both Ac-DEVD-CHO and 2ME2 (IN+2ME2). Fibroblasts at up to passage 3 were used for analysis. Cell activity was measured by the cell counting kit-8. TUNEL staining was used to observe the cell apoptotic morphology. The key apoptosis factors (caspase-3, caspase-8, caspase-9, Bcl-2, Bax, and cytochrome-c) and PCNA expression levels were detected by immunofluorescence analysis and Western blotting. A certain concentration of 2ME2 was also used in group S to evaluate the toxicity. Compared with that in the other groups, 2ME2 significantly inhibited cell activity and led to apoptotic appearance of fibroblasts. In protein analysis, 2ME2 remarkably increased the expression of apoptosis factors and decreased the PCNA expression. Apoptosis levels were reduced by both the caspase inhibitor and 2ME2; thus indicating that the pro-apoptosis effect of 2ME2 was achieved through a caspase-dependent mechanism in keloid fibroblasts. Toxicity assessment showed that 2ME2 had a very low influence on normal skin fibroblasts. 2ME2, considered to be a new promising type of chemotherapy drug, exerts a pro-apoptosis effect by regulating the caspase family and an anti-proliferation effect towards keloid fibroblasts, and it presents low toxicity towards normal fibroblasts in vitro.
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PMID:2-Methoxyestradiol improves the apoptosis level in keloid fibroblasts through caspase-dependent mechanisms in vitro. 3066 47