Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a well-established cellular mechanism for selective cell deletion during development. However, little is known about the expression of an apoptotic pathway and its role in determining the relative sensitivity of the early, pre-gastrula, avian embryo to stress-induced cell death. We examined the sensitivity of avian blastodermal cells to engage in apoptosis upon exposure to etoposide, a topoisomerase II-inhibitor that rapidly and efficiently induces apoptosis in many cell types. We found that while the blastodermal cells are capable of engaging in apoptosis, they are highly resistant to such induction with respect to both concentration of drug required and length of exposure, even when compared to a tumor cell line with a known multi-drug resistant phenotype. Additionally, we assessed the expression of several candidate regulatory genes in blastodiscs from infertile eggs (i.e., maternal RNA transcripts), blastodermal cells immediately following oviposition, and various stages of early development up to gastrulation. This analysis revealed that several genes whose products have anti-apoptotic activity, including bcl-2, bcl-xL, hsp70, grp78 and the glutathione S-transferases, are expressed as early as the stage 1 embryo in the newly oviposited egg. These transcripts are also found in the infertile blastodisc, suggesting a role for maternally derived transcripts in the protection of the oocyte and zygote. Significantly, constitutive levels of hsp70 mRNA exceeded those of the other anti-apoptotic genes in the blastodermal cells. These results contribute to an emerging picture of stress resistance at the earliest stages of avian embryo development which involves multiple anti-apoptotic genes that act at different regulatory points in the apoptotic cascade.
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PMID:Expression of cell death regulatory genes and limited apoptosis induction in avian blastodermal cells. 974 Mar 20

DNA topoisomerase II (topo II) is an essential nuclear enzyme required for chromatin condensation and chromosome segregation during mitosis. Forced overexpression of topo IIalpha was found to cause morphological changes in recipient cells associated with apoptosis. This induction of apoptosis required nuclear localization of topo IIalpha, yet was independent of the DNA cleavage-religation activity of the enzyme. Apoptosis mediated by topo IIalpha deregulation was blocked by overexpression of crmA, a specific inhibitor of certain caspases, but not by bcl-2. topo IIalpha-induced apoptosis was also blocked by overexpression of a dominant-acting mutant of stress-activated protein kinase kinase (SEK1/MKK4) but not by the overexpression of its normal counterpart. Furthermore, apoptosis was blocked by coexpression of a dominant-negative form of the cyclin-dependent kinase cdk2 but not by dominant-negative cdc2. These results provide a rationale for the tight regulation of topo IIalpha levels through the cell cycle in that deregulation of topo IIalpha expression results in apoptotic cell death.
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PMID:Induction of apoptosis by deregulated expression of DNA topoisomerase IIalpha. 978 93

The aim of this study was to identify the molecular mechanism of action of the isoflavone, genistein. Genistein at 0.15 mM caused MCF-7 apoptotic cell death, which was accompanied by cell cycle delay in the G2/M phase. Twenty-four hours post-treatment, 47.3% of the MCF-7 cells accumulated at G2/M, compared with 19.9% in the untreated controls. At 0.15 mM, genistein caused an increase in the steady-state levels of the wild-type tumour suppressor p53, which was attributed to stabilising the tumour suppressor protein, since p53 mRNA levels did not increase. Prior to the upregulation of p53, which became evident within 6 h of genistein treatment, there was increased bcl-2 phosphorylation at 30 min post-treatment. Although early changes (30-120 min) in the phosphotyrosine peptide patterns were not detected, after 24h, genistein inhibited phosphorylation of several peptides. These results suggest that genistein's dual roles of protein tyrosine kinase inhibitor and topoisomerase II inhibitor are essential for the initiation of apoptosis.
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PMID:Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells. 1002 17

Lymphangioma (LA) and congenital pulmonary lymphangiectasis (CPL) are part of a spectrum of lymphatic disorders less well characterized than other vascular tumors and malformations. Recent studies showed proliferative and involutional growth phases for hemangiomas that distinguish them from malformations. We investigated immunohistochemical reactivity and proliferative activity to determine whether a similar diagnostically/prognostically useful pattern exists for LA, comparing LA with CPL as a malformative lesion. Immunohistochemical tests for vimentin, Factor VIII-related protein, CD31, CD34, CD45RO, smooth muscle actin, Type IV collagen, MIB-1, bcl-2, and topoisomerase IIalpha were performed on 20 LAs and 10 cases of CPL. Giemsa staining was also performed to quantitate mast cells. Clinicopathologic correlation was performed by medical record review. LA and CPL shared a similar immunohistochemical profile for vimentin, Factor VIII-related protein, CD31, CD34, smooth muscle actin, CD34, and, to a lesser extent, CD45RO. CD31 and CD34 displayed the most uniform pattern of endothelial reactivity, although CD34 had high background staining. bcl-2 was negative. Four LAs exhibited focal low reactivity for MIB-1 and topoisomerase IIalpha; recent infection and thrombosis were associated conditions. LAs displayed seven-fold more mast cells and more reactive T lymphocytes than did cases of CPL. LA and CPL had similar immunohistochemical profiles; LA resembled vascular malformations more than hemangiomas. CD31 and CD34 were useful for detection of small lymphatics at resection margins of LA, a feature associated with recurrence. MIB-1 and topoisomerase IIalpha expression were associated with inflammatory, thrombotic, or reactive processes and were not diagnostically useful. Abundant mast cells, which also were noted in other soft tissue neoplasms, prompt speculation concerning their role in the growth of LAs.
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PMID:Lymphangioma and congenital pulmonary lymphangiectasis: a histologic, immunohistochemical, and clinicopathologic comparison. 1039 31

The tumor suppressor gene product p53 can bind to and inhibit the helicase activity of the multisubunit transcription-repair factor TFIIH. We previously reported that p53-mediated apoptosis is attenuated in primary human fibroblasts from individuals with Xeroderma Pigmentosum (XP) that harbor mutations in the TFIIH DNA helicases XPD or XPB. In this study we show that apoptosis is reduced and delayed in three XPD lymphoblastoid cell lines (LCLs), but not in an XPD heterozygote LCL, after exposure to doxorubicin, a DNA-damaging agent and topoisomerase II inhibitor frequently used in cancer therapy. Apoptosis was assessed by quantitation of Annexin V binding to exposed phosphatidylserine residues and by caspase-mediated cleavage of Poly(ADP)Ribose Polymerase (PARP). Apoptosis induced by doxorubicin was suppressed in LCLs retrovirally transduced with the Human Papillomavirus 16 E6 oncoprotein, consistent with the hypothesis that this is a p53-dependent process. PARP cleavage was not delayed in XPD LCLs in response to anti-Fas (CD95) antibody-mediated apoptosis, thus, the defect in the apoptotic pathway in these cells lies upstream of caspase activation. Similar changes in the expression of apoptosis-effector genes, p53, and p53-responsive genes p21Cip1/WAF-1/Sid1 (p21), gadd45, bcl-2 and bax were observed in normal and XPD LCLs after treatment with doxorubicin, indicating that delayed apoptosis was not a consequence of defective transcription of these genes. Thus, our studies provide further support to the hypothesis that XPD and p53 can functionally interact in a p53-mediated apoptotic pathway.
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PMID:Drug-induced apoptosis is delayed and reduced in XPD lymphoblastoid cell lines: possible role of TFIIH in p53-mediated apoptotic cell death. 1046 15

Drug resistance is a major problem in patients with small cell lung cancer; in fact, most die of resistant disease, despite an initial response. Several markers of drug resistance have been described in preclinical models, but the mechanism of drug resistance in lung cancer patients remains unknown. The objective of this study was to evaluate the role of the expression of a number of markers of drug resistance, proliferation, and apoptosis in relation to response to chemotherapy and survival in patients with small cell lung cancer. Tumor samples were derived from 93 previously untreated patients who were randomized in a Phase III study to receive cyclophosphamide, epirubicine, and etoposide or cyclophosphamide, epirubicine and vincristine alternating with carboplatin and etoposide. Paraffin-embedded samples, derived from the primary tumor site prior to chemotherapy, were analyzed by immunohistochemistry for expression of markers implicated in drug resistance [topoisomerase (topo) IIalpha, topo IIbeta, and multidrug resistance-associated protein], apoptosis (p53, p21, and bcl-2), or proliferation (Ki67). Response prediction was analyzed by chi2 test and logistic regression analysis; overall and disease-free survival curves were compared by log-rank test and Cox regression analysis. Shorter survival was observed in patients with extensive disease (P = 0.037) and poorer performance status (P = 0.028) and in patients whose tumors expressed high topo IIalpha levels (P = 0.01) and high Ki67 (P = 0.024). By multivariate analysis, the following factors were found to be predictive for worse survival: high expression levels of topo IIalpha, Ki67, and bcl-2; male sex; and extensive disease. High topo IIbeta expression was found to be predictive for lower overall and complete response rate. No relationship between apoptotic pathway markers or MRP and response to chemotherapy was observed. In conclusion, high expression of topo IIalpha was predictive of worse survival, and high expression of topo IIbeta was predictive of lower response rates. Furthermore, lower survival probability was observed in patients with bcl-2-positive tumors. Immunohistochemical assessment of these markers in diagnostic biopsies may give important prognostic information and may help selecting patients in the worse prognostic categories for new therapeutic strategies.
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PMID:Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer. 1047 85

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.
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PMID:Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers. 1115 Mar 76

Several studies have shown that extracellular matrix reduces chemotherapeutic drugs-induced apoptosis in small cell lung cancer cells, myelomas and gliomas. We have investigated the protective effect of defined extracellular matrix components and of extracellular matrix from different cell types (fibroblasts, hepatocytes and intestinal epithelial cells) on the toxicity of three types of chemotherapeutic drugs on colon cancer cells. Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU). the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide. We determined IC50 for the drugs for each of these culture conditions. We also determined the expression of the anti-apoptotic proteins bcl-2 and bcl-x (L) under these culture conditions. We found that stromal ECM protected LiM6 cells from the toxicity of etoposide and LS174T, but not LiM6 cells, from the toxicity of camptothecin. Collagen 1, fibronectin and fibroblast-derived ECM rendered LiM6 cells, but not LS174T, more sensitive to the harmful effect of 5-FU. Both colon cell lines had increased expression of anti-apoptotic proteins bcl-2 and bcl-x(L) when cultured on the various ECMs and with the drugs, but there was no correlation between a protective ECM effect and expression of the anti-apoptotic proteins. Stromal-derived ECM may protect colon cancer cells from etoposide and camptothecin-induced apotosis, through a mechanism that is not bcl-2 or bcl-x(L) dependant.
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PMID:Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines. 1191 83

Several studies have shown that hexavalent chromium [Cr(VI)] induces apoptosis in a variety of in vitro test systems. We instilled intra-tracheally either saline or sodium dichromate (0.25 mg/kg body weight), for three consecutive days, to Sprague-Dawley rats. TUNEL analyses showed a marked increase of the apoptotic index in both bronchial epithelium and lung parenchyma of Cr(VI)-treated rats, but no effect was detected in their liver. In parallel, the expression of 13 out of 18 apoptosis-related genes, evaluated by cDNA array analysis, was significantly enhanced in rat lung. The overexpressed genes included c-Jun N-terminal kinases 1, 2 and 3, bcl-x, bcl-2-associated death promoter and bcl-2-related ovarian killer protein, caspases 1, 3 and 6, DNase I precursor, DNA topoisomerases I and II alpha, and poly(ADP-ribose) polymerase. The enhancement of p53 expression in the lung was borderline to statistical significance. Expressions of bcl-2, bax-alpha, mdm2 and DNA topoisomerase IIB were not enhanced to a significant extent in lung. No induction of gene expression was observed in rat liver. RT-PCR analyses confirmed that Cr(VI) enhances the expression of c-Jun N-terminal kinase 1, caspase 6, and DNase I precursor but not that of bcl-2 in lung, while none of these genes was overexpressed in the liver of Cr(VI)-treated rats. The lack of stimulation of apoptosis in the liver parallels the failure of Cr(VI) to produce genotoxic damage, as we previously observed under identical experimental conditions. These negative findings may be ascribed to reduction of Cr(VI) to Cr(III) when traveling from the respiratory tract to the liver. On the other hand, induction of apoptosis in the respiratory tract parallels the occurrence of genotoxic effects and oxidative DNA damage produced by Cr(VI) in the same tissue. As previously shown in another laboratory, Cr(VI) did not induce lung tumors after 30 months of administration of the same daily dose. Therefore, apoptosis is likely to provide a protective mechanism at a post-genotoxic stage of Cr(VI) carcinogenesis.
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PMID:Induction of apoptosis in the lung but not in the liver of rats receiving intra-tracheal instillations of chromium(VI). 1196 Sep 10

Numerous studies demonstrate that the chemopreventive effect of non-steroidal anti-inflammatory drugs on colon cancer is mediated through inhibition of cell growth and induction of apoptosis. For these effects non-steroidal anti-inflammatory drugs have been recently employed as sensitising agents in chemotherapy. We have shown previously that treatments with aspirin and NS-398, a cyclo-oxygenase-2 selective inhibitor, affect proliferation, differentiation and apoptosis of the human colon adenocarcinoma Caco-2 cells. In the present study, we have evaluated the effects of aspirin and NS-398 non-steroidal anti-inflammatory drugs on sensitivity of Caco-2 cells to irinotecan (CPT 11) and etoposide (Vp-16) topoisomerase poisons. We find that aspirin co-treatment is able to prevent anticancer drug-induced toxicity, whereas NS-398 co-treatment poorly affects anticancer drug-induced apoptosis. These effects correlate with the different ability of aspirin and NS-398 to interfere with cell cycle during anticancer drug co-treatment. Furthermore, aspirin treatment is associated with an increase in bcl-2 expression, which persists in the presence of the anticancer drugs. Our data indicate that aspirin, but not NS-398, determines a cell cycle arrest associated with death suppression. This provides a plausible mechanism for the inhibition of apoptosis and increase in survival observed in anticancer drug and aspirin co-treatment.
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PMID:Effect of non-steroidal anti-inflammatory drugs on colon carcinoma Caco-2 cell responsiveness to topoisomerase inhibitor drugs. 1198 87


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