Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Electrophoresis of cytosol prepared from normal and malignant tissue samples of uterine cervix and endometrium revealed interesting differences which may be relevant to the characteristic alterations in glucose metabolism associated with tumour development. Hexokinase II was detected in 30% of the cancer material from both sources, but in none of the samples of normal cervix. A duplet band of 6-phosphogluconate dehydrognease was seen in the majority of the cancer samples but in no sample of normal cervix; it appeared to be partly due to ageing of the sample, and is not phenotypically related to the malignant process. Analysis of genetic variance for phosphoglucomutase at the PGM1 locus revealed a highly significant excess of the PGM1-1 phenotype in patients with cancer of the endometrium, which may reflect susceptibility to endometrial cancer in patients with this phenotype. At the PGM2 locus, samples of malignant cervix were deficient in "Band f" compared with normal cervix samples, all of which showed this band. Conversely, gene products of the PGM3 locus were found in most samples of malignant cervix and a small minority of normal cervix samples. Compared with the isomorphic distribution of lactate dehydrogenase enzymes in normal uterine tissue, cancers showed a shift towards either a more anodal or a more cathodal pattern. The former may be associated with tumours enjoying a good oxygen supply, and the latter with tumours which, because of their depth or poor blood supply have to function under less aerobic conditions.
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PMID:Isoenzymes of hexokinase, 6-phosphogluconate dehydrogenase, phosphoglucomutase and lactate dehydrogenase in uterine cancer. 50 67

Estrogen replacement therapy has been correlated with an increased risk of developing breast or endometrial cancer. 4-Hydroxyequilenin (4-OHEN) is a catechol metabolite of equilenin which is a minor component of the estrogen replacement formulation marketed under the name of Premarin (Wyeth-Ayerst). Previously, we showed that 4-OHEN autoxidizes to quinoids which can consume reducing equivalents and molecular oxygen, are potent cytotoxins, and cause a variety of damage to DNA, including formation of bulky stable adducts, apurinic sites, and oxidation of the phosphate-sugar backbone and purine/pyrimidine bases [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. All of these deleterious effects could contribute to the cytotoxic and genotoxic effects of equilenin in vivo. In the study presented here, we examined the relative toxicity of 4-OHEN in estrogen receptor (ER) positive cells (MCF-7 and S30) compared to that in breast cancer cells without the estrogen receptor (MDA-MB-231). The data showed that 4-OHEN was 4-fold more toxic to MCF-7 cells (LC(50) = 6.0 +/- 0. 2 microM) and 6-fold more toxic to S30 cells (LC(50) = 4.0 +/- 0.1 microM) than to MDA-MB-231 cells (LC(50) = 24 +/- 0.3 microM). Using the single-cell gel electrophoresis assay (comet assay) to assess DNA damage, we found that 4-OHEN causes concentration-dependent DNA single-strand cleavage in all three cell lines, and this effect could be enhanced by agents which catalyze redox cycling (NADH) or deplete cellular GSH (diethyl maleate). In addition, the ER(+) cell lines (MCF-7 and S30) were considerably more sensitive to induction of DNA damage by 4-OHEN than the ER(-) cells (MDA-MB-231). 4-OHEN also caused a concentration-dependent increase in the amount of mutagenic lesion 8-oxo-dG in the S30 cells as determined by LC/MS-MS. Cell morphology assays showed that 4-OHEN induces apoptosis in these cell lines. As observed with the toxicity assay and the comet assay, the ER(+) cells were more sensitive to induction of apoptosis by 4-OHEN than MDA-MB-231 cells. Finally, the endogenous catechol estrogen metabolite 4-hydroxyestrone (4-OHE) was considerably less effective at inducing DNA damage and apoptosis in breast cancer cell lines than 4-OHEN. Our data suggest that the cytotoxic effects of 4-OHEN may be related to its ability to induce DNA damage and apoptosis in hormone sensitive cells in vivo, and these effects may be potentiated by the estrogen receptor.
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PMID:A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines. 1081 50

In cancer patients impaired blood rheology in the presence of coagulation activation may reduce blood flow in the vascular microcirculation that favors thrombosis but may also support tumor progression and metastasis. In 451 patients with gynecological cancer and 177 patients with corresponding benign tumor disease preoperatively, during adjuvant treatment, when venous thrombosis (VT) or cancer progression was diagnosed hematocrit (micro centrifuge), hemoglobin, leukocytes, platelets (Coulter Counter); red blood cell (RBC) aggregation (aggr.) during stasis and low shear conditions (MA 1, Myrenne), plasma viscosity (viscosimeter KSPV 1 Fresenius), and fibrinogen (Multifibren Behring Dade) were investigated. One hundred and twelve healthy women served as controls. Preoperatively, mean plasma viscosity (pv) was significantly higher in cancer patients as compared to patients with the corresponding benign tumor disease (breast cancer: n = 261; pv = 1.32 vs. 1.27 mPa s; p = 0.023; ovarian cancer: n = 68; pv = 1.39 vs. 1.31 mPa s; p < 0.001; endometrial cancer: n = 70; pv = 1.37 vs. 1.25 mPa s; p < 0.001; cervical cancer: n = 52; pv = 1.33 vs. 1.26 mPa s; p = 0.004). RBC aggr. was significantly lower in controls compared to the preoperative values in cancer patients but mean (median) values (RBC aggr. stasis < 21) were within the normal range in all. Preoperatively, plasma viscosity was a significant risk factor for the overall survival in ovarian cancer patients (p = 0.02) and for subsequent thrombosis in ovarian (p = 0.02) and cervical cancer patients (p = 0.007). In the multivariate analysis plasma viscosity was an independent prognostic marker for the overall survival of breast cancer patients (r = 99.45; 95% CI: 7.32-980.2; p < 0.0001). An optimized preoperative cut-off value above 1.40 mPa s (Log-Rank-test) was significantly associated with poor outcome in the Kaplan-Mayer survival estimates, even in node-negative breast cancer. In gynecologic cancer patients the combination of an increase in RBC aggregation and plasma viscosity impairs blood-flow-properties and may induce hypoxia in the microcirculation that favors thrombosis, settlement of tumor-cells and thus metastasis. Improvement of blood fluidity and thus oxygen transfer in the tumor-vascular-microcirculation may increase susceptibility of systemic anti-cancer therapy.
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PMID:Association between blood rheology, thrombosis and cancer survival in patients with gynecologic malignancy. 1083 Oct 62

Tamoxifen is a major drug used for adjuvant chemotherapy of breast cancer; however, its use has been associated with a small but significant increase in risk of endometrial cancer. In rats, tamoxifen is a hepatocarcinogen, and DNA adducts have been observed in both rat and human tissues. Tamoxifen has been shown previously to be metabolized to reactive products that have the potential to form protein and DNA adducts. Previous studies have suggested a role for P450 3A4 in protein adduct formation in human liver microsomes, via a catechol intermediate; however, no clear correlation was seen between P450 3A4 content of human liver microsomes and adduct formation. In the present study, we investigated the P450 forms responsible for covalent drug-protein adduct formation and the possibility that covalent adduct formation might occur via alternative pathways to catechol formation. Recombinant P450 3A4 catalyzed adduct formation, and this correlated with the level of uncoupling in the P450 incubation, consistent with a role of reactive oxygen species in potentiating adduct formation after enzymatic formation of the catechol metabolite. Whereas P450s 1A1, 2D6, and 3A5 generated catechol metabolite, no covalent adduct formation was observed with these forms. By contrast, P450 2B6, 2C19, and rat liver microsomes catalyzed drug-protein adduct formation but not catechol formation. Drug protein adducts formed specifically with P450 3A4 in incubations using membranes isolated from bacteria expressing P450 3A4 and reductase, as well as in reconstitutions of purified 3A4, suggesting that the electrophilic species reacted preferentially with the P450 enzymes concerned.
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PMID:Bioactivation of tamoxifen by recombinant human cytochrome p450 enzymes. 1201 81

Oxygenation of tumor tissue has recently been assed an important prerequisite for the effectiveness of radiotherapy in cervical cancer. Hyperviscosity is a common phenomenon in malignancy and a cause of reduced oxygen transport capacity that would favour tissue hypoxia. Hemorheological variables were serially tested preoperatively, during four cycles of fractionated adjuvant IR(192) HDR after loading radiation (HDR-AL) of the vaginal vault (weekly intervals), and 6 months postoperatively in patients with cervical (n=12) and endometrial cancer (n=26). Women who were scheduled for benign tumor surgery served as controls (n=29). Preoperatively, in cervical and endometrial cancer patients, mean plasma viscosity (PV: 1.31+/-0.1 mPa s; p<0.05; 1.35+/-0.13 mPa s; p<0.001) and fibrinogen levels (383+/-46 mg/dL; p<0.05; 379+/-117 mg/dL; p<0.05) were higher as compared to the controls (1.25+/-0.07 mPa s; 314+/-89 mg/dL). Red blood cell aggregation at low shear and stasis (RBC agg.: 15.7+/-5.6; p<0.05; 29.6+/-9.1; p<0.05) was higher in endometrial cancer patients as compared to the controls (13.7+/-3.4; 25.3+/-5.6). Postoperatively PV decreased in endometrial cancer patients and transiently increased in cervical cancer patients. After the third session of irradiation in both cancer groups, PV regained and at the 6-month checkup, levels were higher as compared to the values before surgery. Postoperatively fibrinogen levels increased and remained higher throughout HDR-AL and 6 months postoperatively. After surgery and during irradiation, anemia persisted in both cancer groups while hematocrit recovered after 6 months in endometrial cancer patients. Thrombosis was diagnosed in three patients postoperatively (7.9 %) but in none during HDR-AL. While a temporary reduction of hyperviscosity is found postoperatively and during HDR-AL in uterine cancer patients, 6 months after surgery RBC aggregation, PV, and hematocrit returned to the pretreatment range.
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PMID:Monitoring of rheologic variables during postoperative high-dose brachytherapy for uterine cancer. 1524 81

The metabolism of solid tumors is associated with high lactate production while growing in oxygen (aerobic glycolysis) suggesting that tumors may have defects in mitochondrial function. The mitochondria produce cellular energy by oxidative phosphorylation (OXPHOS), generate reactive oxygen species (ROS) as a by-product, and regulate apoptosis via the mitochondrial permeability transition pore (mtPTP). The mitochondria are assembled from both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) genes. The mtDNA codes for 37 genes essential of OXPHOS, is present in thousands of copies per cell, and has a very high mutations rate. In humans, severe mtDNA mutations result in multisystem disease, while some functional population-specific polymorphisms appear to have permitted humans to adapt to new environments. Mutations in the nDNA-encoded mitochondrial genes for fumarate hydratase and succinate dehydrogenase have been linked to uterine leiomyomas and paragangliomas, and cancer cells have been shown to induce hexokinase II which harnesses OXPHOS adenosine triphosphate (ATP) production to drive glycolysis. Germline mtDNA mutations at nucleotides 10398 and 16189 have been associated with breast cancer and endometrial cancer. Tumor mtDNA somatic mutations range from severe insertion-deletion and chain termination mutations to mild missense mutations. Surprisingly, of the 190 tumor-specific somatic mtDNA mutations reported, 72% are also mtDNA sequence variants found in the general population. These include 52% of the tumor somatic mRNA missense mutations, 83% of the tRNA mutations, 38% of the rRNA mutations, and 85% of the control region mutations. Some associations might reflect mtDNA sequencing errors, but analysis of several of the tumor-specific somatic missense mutations with population counterparts appear legitimate. Therefore, mtDNA mutations in tumors may fall into two main classes: (1) severe mutations that inhibit OXPHOS, increase ROS production and promote tumor cell proliferation and (2) milder mutations that may permit tumors to adapt to new environments. The former may be lost during subsequent tumor oxygenation while the latter may become fixed. Hence, mitochondrial dysfunction does appear to be a factor in cancer etiology, an insight that may suggest new approaches for diagnosis and treatment.
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PMID:Mitochondrial mutations in cancer. 1689 79

The biological functions and reaction pathways of lipocalins in mammalian system were sought. Mouse uterine 24p3 protein is a secreted lipocalin from mouse uterus. To evaluate the effect of uterine 24p3 protein on the reproductive system, endometrial carcinoma cell line (RL95-2) was an experimental target for achieving the in vitro study. The cells were treated with 0.75 microM dexamethasone (DEX) or under serum-free medium to mimic the stress environment for various time periods, then employing Western blot to measure the 24p3 protein secretion. It showed the time-dependent induction effect on 24p3 protein and suggested the level of protein secretion correlating to environmental stress. Furthermore, the supplementation of 24p3 protein to the medium accompanied the reduction of cell viability. It showed that the 24p3 protein may be a death factor under conditional media via PI and annexinV-FITC assay. Based on the autocrine hypothesis, we investigated the effect of 24p3 protein on cultured RL95-2 cells upon the 24p3 protein interaction. We have demonstrated significant increase in intracellular reactive oxygen species upon 24p3 protein interaction. While the changes of mitochondrial membrane potential and cytochrome c release from mitochondria occurred, the activities of caspase-8, -9 and -3 were found to have increased. The condensation of DNA was occurred suggesting that 24p3 protein induced irreparable DNA damage, which in turn triggered the process of apoptosis. It shows evidence for the direct effect of this protein on endometrial cells. These findings suggest that 24p3 protein creates an intracellular oxidative environment that induces apoptosis in RL95-2 cells.
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PMID:Apoptosis induced by uterine 24p3 protein in endometrial carcinoma cell line. 1742 78

We have recently demonstrated that proteasome inhibitors can be effective in inducing apoptotic cell death in endometrial carcinoma cell lines and primary culture explants. Increasing evidence suggests that reactive oxygen species are responsible for proteasome inhibitor-induced cell killing. Antioxidants can thus block apoptosis (cell death) triggered by proteasome inhibition. Here, we have evaluated the effects of different antioxidants (edaravone and tiron) on endometrial carcinoma cells treated with aldehyde proteasome inhibitors (MG-132 or ALLN), the boronic acid-based proteasome inhibitor (bortezomib) and the epoxyketone, epoxomicin. We show that tiron specifically inhibited the cytotoxic effects of bortezomib, whereas edaravone inhibited cell death caused by aldehyde-based proteasome inhibitors. We have, however, found that edaravone completely inhibited accumulation of ubiquitin and proteasome activity decrease caused by MG-132 or ALLN, but not by bortezomib. Conversely, tiron inhibited the ubiquitin accumulation and proteasome activity decrease caused by bortezomib. These results suggest that edaravone and tiron rescue cells of proteasome inhibitors from cell death, by inhibiting blockade of proteasome caused by MG-132 and ALLN or bortezomib, respectively. We also tested other antioxidants, and we found that vitamin C inhibited bortezomib-induced cell death. Similar to tiron, vitamin C inhibited cell death by blocking the ability of bortezomib to inhibit the proteasome. Until now, all the antioxidants that blocked proteasome inhibitor-induced cell death also blocked the proteasome inhibitor mechanism of action.
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PMID:Antioxidants block proteasome inhibitor function in endometrial carcinoma cells. 1817 7

Tumor angiogenesis is a process where new blood vessels are formed from preexisting ones, resulting in several pathologies. Solid tumors induce angiogenesis to obtain the required nutrients and oxygen. Otherwise, tumors do not grow beyond 2 to 3 mm in diameter. Cyclooxygenase-2, an inducible enzyme important in inflammation, catalyzes the production of prostanoids from arachidonic acid. Cyclooxygenase-2 plays an important role in several cancer types, including colorectal, gastric, prostate, breast, lung, and endometrial cancer. Besides, cyclooxygenase-2 has been implicated in the progression and angiogenesis of cancers. Cyclooxygenase-2 inhibitors have been used to block angiogenesis and tumor proliferation. In this review, the recent studies related to the role of cyclooxygenase-2 in several cancer types and tumor-induced angiogenesis were compiled.
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PMID:Cyclooxygenase-2 in cancer and angiogenesis. 1850 47

Prolonged exposure to unopposed estrogens is a major risk factor for the development of endometrial cancer. Oxidative metabolism of estradiol (E(2)) into the catecholestrogens (CEs), 4-hydroxyestradiol (4-OHE(2)) and 2-hydroxyestradiol (2-OHE(2)), may play an important role in estrogen carcinogenicity. CEs can be oxidized to the corresponding ortho-quinone derivatives with concomitant formation of the reactive oxygen species (ROS). Catechol-O-methyltransferase (COMT) is the major enzyme involved in the detoxification of CEs in extrahepatic tissues. We investigated the potential of E(2), 2-OHE(2) and 4-OHE(2) to induce microsatellite instability (MSI) and neoplastic transformation of immortalized human endometrial glandular (EM) cells. We also investigated the functional significance of COMT gene expression on modulating the effects of E(2) and CEs in EM cells. Our data indicated that E(2) and 4-OHE(2) induce MSI, ROS and neoplastic transformation in EM cells. The capacity of E(2) and its catechol metabolites to induce MSI, ROS and neoplastic transformation in EM cells is ranked as follows: 4-OHE(2) > E(2) > 2-OHE(2). Knockdown of COMT expression in EM cells resulted in increased estrogenic milieu and increased estrogen-induced cell proliferation. More importantly, knockdown of COMT increased the propensity of E(2) or CEs to induce ROS, MSI and neoplastic transformation of EM cells. In contrast, overexpression of COMT in EM cells significantly reduced the cellular estrogenic milieu and protected against E(2)- or CEs-induced, ROS, MSI and neoplastic transformation. The capacity of E(2) or CEs to induce neoplastic transformation of human endometrial glandular cells in vitro may suggest that E(2)-induced endometrial cancer is mediated by its metabolism into CEs. Our study clearly indicates that COMT gene expression plays a critical role in modulating the hormonal and carcinogenic effects of E(2) and CEs and, consequently, modifies the risk for E(2)-induced endometrial cancer. To the best of our knowledge, this is the first study to (i) demonstrate the potential capacity of estrogen and its catechol metabolites to induce neoplastic transformation of immortalized human endometrial glandular cells; and (ii) illustrate the important role of COMT gene expression in protecting against E(2)-induced endometrial cancer.
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PMID:Catecholestrogens induce oxidative stress and malignant transformation in human endometrial glandular cells: protective effect of catechol-O-methyltransferase. 1856 89


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