Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that solamargine (SM), the major steroidal glycoalkaloid extracted from Chinese herb Solanum plants, reveals down-regulation of HER2 and up-regulation of Fas and tumor necrosis factor receptor (TNFR) expressions, triggers the mitochondria-mediated cell apoptosis pathway, and sensitizes human nonsmall cell lung cancer (NSCLC) H441 and A549 adenocarcinoma cells to chemotherapy. The present study shows that SM enhances HER2 expression in NSCLC large cell carcinoma H661 and small cell lung cancer (SCLC) H69 cells and may increase the susceptibility of the cells to trastuzumab, the humanized anti-HER2 antibody. The combinational treatment of SM and trastuzumab synergistically augments and inhibits H661 and H69 cell proliferation. After treatment with SM, coexpression of HER2 and topoisomerase IIalpha (TOP2A) H661 and H69 cells is more sensitive to the TOP2 inhibitor, epirubicin. The combinatory use of low concentrations of SM with the low-toxic epirubicin accelerated greater apoptotic cell death than each drug did alone in H661 and H69 cells. Relevant studies have shown that HER2 overexpressing cancer cells are more resistant than HER2 low-expressing cells to the chemotherapeutic agent and tumor necrosis factor-induced apoptosis. These investigations have indicated that HER2 overexpression does not suffice to induce intrinsic and pleomorphic drug resistance. The data presented herein suggest that the expression of HER2 did not influence the SM-induced apoptosis of different types of lung cancer cells and that the SM up-regulation of HER2 and TOP2A expressions simultaneously augmented trastuzumab and epirubicin-induced deaths of lung cancer H661 and H69 cells.
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PMID:Solamargine enhances HER2 expression and increases the susceptibility of human lung cancer H661 and H69 cells to trastuzumab and epirubicin. 1807 28

Cytotoxic action (tumor cell killing) and carcinogenic side effect (therapy-related secondary leukemia) of etoposide are closely related to its ability in stabilizing topoisomerase II cleavable complex (TOP2cc), a unique form of protein-linked DNA break. How cells process and detect TOP2-concealed DNA damage for the activation of downstream cellular responses remains unclear. Here, we showed proteasomal degradation of both TOP2 isozymes in a transcription-dependent manner upon etoposide treatment. Downregulation of TOP2 was preferentially associated with proteasomal removal of TOP2 in TOP2cc rather than proteolysis of free TOP2. Interestingly, blockage of TOP2 downregulation in TOP2cc also caused reduction in etoposide-induced activation of DNA damage molecules, an observation suggesting that the processing pathways of TOP2cc are involved in activation of etoposide-induced cellular responses. In this regard, we observed two TOP2cc processing pathways, replication- and transcription-initiated processing (RIP and TIP) with proteasome involved in the latter. Importantly, two processing pathways contributed to differential activation of various DNA damage signaling and downstream cellular responses. Etoposide-induced phosphorylation of p53 relied mainly on RIP, whereas activation of Chk1, Chk2 depended largely on TIP. Both RIP and TIP played roles in activating non-homologous end joining pathway, while only RIP modulated etoposide-induced cell killing in a p53-dependent manner. Collectively, our results are consistent with the notion that protein-linked DNA breakage (e.g., TOP2cc) requires processing pathways for initiating downstream DNA damage detection, repair as well as cell death programs.
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PMID:Cellular processing pathways contribute to the activation of etoposide-induced DNA damage responses. 1820 27

HER2 overexpression or amplification has been shown to be associated with a poor prognostic effect in women with breast cancer. At least eight analyses based on randomized trials have examined the relationship between HER2 and the differential effect of anthracycline compared with non-anthracycline-containing regimens. Only three of these studies were sufficiently powered to show a significant interaction between HER2 and anthracycline- versus non-anthracycline-containing treatments, but because all of the study results tended to be in the same direction, it is not surprising that three recent meta-analyses of published data have suggested that anthracycline-containing regimens provide more benefit than non-anthracycline-containing regimens in women whose tumors are overexpressed or amplified (positive) for HER2. Since topoisomerase II is a known target of the anthracyclines, it has been postulated that this relationship is actually based on the proximity of HER2 to the topoisomerase II alpha gene (TOP2A) in the 17q chromosome. At least four recent studies have suggested that deletion and amplification of the TOP2A gene are associated with poor prognosis and are predictive of greater response to anthracycline-containing than to non-anthracycline-containing regimens. However, in at least one of those studies, HER2 positivity was as or more predictive. Although it has been suggested that HER2 positivity is predictive of better response to higher-dose anthracycline-containing regimens compared with standard anthracycline-containing regimens and to taxane- compared with non-taxane-containing regimens, these relationships have not been robust or consistent. Additional studies will be required to clarify these relationships.
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PMID:HER-2 and topoisomerase II as predictors of response to chemotherapy. 1848 78

Epirubicin exerts its anti-tumor effect through binding to topoisomerase IIalpha (TOP2A) and inducing DNA double-strand breaks. BRCA1 is involved in the repair of these breaks. We investigated the relationship between TOP2A or BRCA1 immunohistochemical expression and pathological response in 108 primary breast cancers treated with epirubicin-based regimens. The pCR (pathological complete response) rate for TOP2A-positive (17%) was significantly (P < 0.005) higher than for TOP2A-negative (2%), while the pCR rate for BRCA1-negative (11%) was non-significantly higher than for BRCA1-positive (5%). The pCR rate of TOP2A-positive and BRCA1-negative (30%) was significantly higher than for TOP2A-negative and BRCA1-positive (3%; P < 0.05), or TOP2A-negative and BRCA1-negative (0%; P < 0.005). The TOP2A-positive and BRCA1-negative phenotype associates with a favorable response to epirubicin-based regimens.
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PMID:Topoisomerase IIalpha-positive and BRCA1-negative phenotype: association with favorable response to epirubicin-based regimens for human breast cancers. 1828 Jun 44

Resistance to topoisomerase I (TOP1)-targeting drugs such as topotecan often involves upregulation of topoisomerase II (TOP2), with accompanying increased sensitivity to TOP2-targeting drugs such as etoposide. This trial was designed to investigate sequential topoisomerase targeting in the treatment of patients with high-risk acute myelogenous leukemia. An initial cohort of patients received topotecan and cytosine arabinoside daily for 5 days. Serial samples of circulating mononuclear cells were examined to evaluate peak elevations of TOP2-alpha protein expression. In subsequent cohorts, etoposide was administered daily for 3 days, beginning 6 h after initiation of the topotecan infusion. The etoposide dose was escalated to determine a maximum-tolerated dose. Circulating mononuclear cells were analyzed for TOP1 mutations and ABCG2 protein expression. In addition, systemic and intracellular topotecan concentrations were measured. Thirty-one patients were enrolled. On the basis of TOP1-alpha protein levels in three patients with peripheral blast counts greater than 50%, etoposide administration began 6 h after initiation of the topotecan/cytosine arabinoside infusion. Using this schedule of administration, the maximum-tolerated dose of etoposide was 90 mg/m. No TOP1 mutations were identified, but increases in ABCG2 expression during the infusion were observed in mononuclear cells from two of four evaluable patients. Administration of etoposide 6 h after initiation of a topotecan/cytosine arabinoside infusion is feasible and is associated with clinical activity. Analysis of TOP2-alpha protein levels in this small number of patients indicated that peak increases occurred earlier than expected based on earlier publications. Upregulation of ABCG2 was detected in circulating cells and may represent an inducible form of drug resistance that should be investigated further.
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PMID:Sequential topoisomerase targeting and analysis of mechanisms of resistance to topotecan in patients with acute myelogenous leukemia. 1845 51

Pure invasive micropapillary carcinoma (MPC) is a special histological type that accounts for 0.7-3% of all breast cancers. MPC has a distinctive growth pattern and a more aggressive clinical behaviour than invasive ductal carcinomas of no special type (IDC-NSTs). To define the molecular characteristics of MPCs, we profiled a series of 12 MPCs and 24 grade and oestrogen receptor (ER)-matched IDC-NSTs using high-resolution microarray comparative genomic hybridization (aCGH). In addition, we generated a tissue microarray containing a series of 24 MPCs and performed immunohistochemical analysis with ER, PR, Ki-67, HER2, CK5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1, E-cadherin, and beta-catenin antibodies. In situ hybridization probes were employed to evaluate the prevalence of amplification of HER2, TOP2A, EGFR, CCND1, MYC, ESR1, and FGFR1 genes. aCGH analysis demonstrated that MPCs significantly differed from IDC-NSTs at the genomic level. Gains of 1q, 2q, 4p, 6p, 6q23.2-q27, 7p, 7q, 8p, 8q, 9p, 10p, 11q, 12p, 12q, 16p, 17p, 17q, 19p, 20p, 20q, and 21q, and losses of 1p, 2p, 6q11.1-q16.3, 6q21-q22.1, 9p, 11p, 15q, and 19q were more prevalent in MPCs. High-level gains/amplifications of 8p12-p11, 8q12, 8q13, 8q21, 8q23, 8q24, 17q21, 17q23, and 20q13 were significantly associated with MPCs. A comparison between 24 MPCs and a series of 48 grade and ER-matched IDC-NSTs revealed that high cyclin D1 expression, high proliferation rates, and MYC (8q24) amplification were significantly associated with MPCs. Our results demonstrate that MPCs have distinct histological features and molecular genetic profiles supporting the contention that they constitute a distinct pathological entity.
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PMID:Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. 1848 83

Trastuzumab is used for breast cancer patients with high expression levels of HER2 (human epidermal growth factor receptor 2)/neu; however, it has no effect on cancers with low levels of HER2/neu. SM (solamargine), a major steroidal alkaloid glycoside purified from Solanum incanum, triggered apoptosis of breast cancer cells (MCF-7 and SK-BR-3 cells) and non-cancerous breast epithelial cells (HBL-100 cells) within 3 h. To extend the application of trastuzumab in breast cancer patients, the regulation of HER2/neu expression by SM was investigated. SM significantly up-regulates HER2/neu expression in breast cancer cells with low and high expression levels of HER2/neu, and synergistically enhanced the effect of trastuzumab in inhibiting cell proliferation. Additionally, HER2/neu and TOP2A [TopoII (topoisomerase II) alpha] genes share the same amplicon on an identical chromosome. Notably, SM co-regulates HER2/neu and TopoIIalpha expression markedly, and enhances TopoII inhibitor-EPI (epirubicin)-induced cytotoxicity to breast cancer cells.
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PMID:Solamargine induces apoptosis and enhances susceptibility to trastuzumab and epirubicin in breast cancer cells with low or high expression levels of HER2/neu. 1869 74

Topoisomerase IIalpha is a nuclear enzyme that regulates the tertiary structure of DNA. The influence of topoisomerase IIalpha gene (TOP2A) or protein alterations on disease progression and treatment response in colorectal cancer (CRC) is unknown. The study investigated the clinical relevance of topoisomerase IIalpha in CRC using in vivo and in vitro models. Differentially expressed genes in early and late-stage CRC were identified by array comparative genomic hybridization (CGH). Cellular location of gene amplifications was determined by fluorescence in situ hybridization (FISH). Topoisomerase IIalpha levels, proliferation index, and HER2 expression were examined in 228 colorectal tumors by immunohistochemistry. Overexpression of topoisomerase IIalpha in vitro was achieved by liposome-based transfection. Cell growth inhibition and apoptosis were quantified using the crystal violet assay and flow cytometry, respectively, in response to drug treatment. Amplification of TOP2A was identified in 3 (7.7%) tumors using array CGH and confirmed using FISH. At the protein level, topoisomerase IIalpha staining was observed in 157 (69%) tumors, and both staining and intensity levels were associated with an aggressive tumor phenotype (p values 0.04 and 0.005, respectively). Using logistic regression analysis, topoisomerase IIalpha remained significantly associated with advanced tumor stage when corrected for tumor proliferation (p=0.007) and differentiation (p=0.001). No association was identified between topoisomerase IIalpha and HER2. In vitro, overexpression of topoisomerase IIalpha was associated with resistance to irinotecan (p=0.001) and etoposide chemotherapy (p=0.03), an effect mediated by inhibition of apoptosis. Topoisomerase IIalpha overexpression is significantly associated with alterations in tumor behavior and response to drug treatment in CRC. Our results suggest that gene amplification may represent an important mechanism underlying these changes.
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PMID:Increased topoisomerase IIalpha expression in colorectal cancer is associated with advanced disease and chemotherapeutic resistance via inhibition of apoptosis. 1911 88

In the past decade, a considerable effort has been made to identify molecular markers that predict anthracycline activity. A number of retrospective studies that evaluated the clinical activity of anthracyclines according to HER2 status suggested that the additional benefit of these agents, as compared with non-anthracycline- based chemotherapy, is confined to HER2-positive tumors. More recently, 2 meta-analyses, based on abstracted data, have reinforced this concept, challenging the use of adjuvant anthracyclines in patients with HER2-negative tumors. Additional data suggested that patients who derive the largest clinical benefit from anthracycline-based chemotherapy have TOP2A gene-amplified tumors. The last hypothesis is based on the fact that topoisomerase IIalpha protein is the molecular target of Topo II inhibitors such as anthracyclines. The TOP2A gene is located on chromosome 17q12-17q21, next to the HER2/neu gene. TOP2A gene aberrations (amplifications or deletions) are more frequent in HER2/neu-amplified than in HER2/neu-nonamplified tumors. Approximately 35% and 25% of HER2/neu-amplified tumors carry TOP2A gene amplifications and deletions, respectively; however, although TOP2A gene aberrations are detected most frequently in HER2- amplified tumors, topoisomerase IIalpha protein overexpression (largely regulated by proliferation signals) and DNA repair dysfunctions are observed in different breast cancer subtypes, independent of HER2 status. This finding suggests that hypersensitivity to anthracyclines might not be confined to HER2-positive tumors, and as a consequence, some patients with HER2-negative disease also could derive clinically relevant benefit from these compounds.
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PMID:New understanding of the role of anthracyclines in early-stage breast cancer: patient selection considerations. 1915 39

The histopathologic distinction of cervical adenocarcinoma in situ (AIS) and invasive adenocarcinoma (AC) from some benign endocervical lesions can be challenging. The ProEx C antibody reagent targets nuclear proteins (minichromosome maintenance protein 2, MCM2 and topoisomerase II-alpha, TOP2A), which are over expressed during the aberrant S-phase induction of HPV infected and neoplastic cells. In this immunohistochemical study the utility of the ProEx C reagent in distinguishing AIS and AC from a variety of non-neoplastic glandular lesions was examined. ProEx C immunohistochemical staining was performed on sections from formalin-fixed, paraffin-embedded tissue of 65 cervical tissues including 48 non-neoplastic cervices (normal [n=10], microglandular hyperplasia [n=10], tubal metaplasia [n=11], cervical endometriosis [n=7], reactive endocervix [n=10]) and 17 cervices with glandular malignancy (AIS [n=12] and AC [n=5]). Both intensity and prevalence of immunoreactivity was scored. The median and distribution of scores for both prevalence and intensity was compared for AIS versus each of the 5 benign cervical lesions using a Mann-Whitney U test. The median and distribution of prevalence of immunohistochemical staining for AIS was different from all benign mimics, but the intensity of staining for AIS did overlap with some mimics as it was not significantly different from endometriosis, microglandular hyperplasia, and reactive endocervix. ProEx C reagent has potential as an adjunctive testing tool in the histopathologic diagnosis of both AIS and AC, particularly in difficult cases with small biopsies or foci of disease.
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PMID:A pilot evaluation of a novel immunohistochemical assay for topoisomerase II-alpha and minichromosome maintenance protein 2 expression (ProEx C) in cervical adenocarcinoma in situ, adenocarcinoma, and benign glandular mimics. 1918 25


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