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)

The mechanism of Adriamycin (ADR) induced cytotoxicity is not completely understood. While a variety of mechanisms have been proposed, the production of free radicals by redox cycling of the semiquinone has been implicated in cytotoxicity, specifically for cardiotoxicity. To determine whether a scavenger of free radicals would modify the cytotoxicity of ADR, the benzoic acid derivative 3,4-dihydroxybenzoic acid (DHB) was investigated for its ability to protect against ADR-induced cytotoxicity and DNA double strand breaks in Chinese hamster V79 cells. V79 cells were treated with ADR, or its non-redox cycling analog iminodaunomycin, in the presence or absence of DHB. DHB provided significant protection (dose-modifying factor greater than 2.5 for ADR, and nearly 2 for iminodaunomycin) and also caused a dose-dependent decrease in DNA double strand breaks as measured by pulsed field gel electrophoresis. Assays of topoisomerase II activity showed that DHB inhibited topoisomerase II in a concentration-dependent manner, but did not inhibit topoisomerase I. Another non-toxic topoisomerase II inhibitor, the radioprotector WR-1065, also protected against ADR-induced cytotoxicity. These data identify DHB as a non-toxic inhibitor of DNA topoisomerase II and suggest that much of the cytotoxicity of ADR in actively growing V79 cells is due to mechanisms other than redox cycling by the semiquinone.
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PMID:Protection against Adriamycin cytotoxicity and inhibition of DNA topoisomerase II activity by 3,4-dihydroxybenzoic acid. 1279 89

Chloroethylaminoanthraquinones are described with intercalating and alkylating capacity that potentially covalently cross-link topoisomerase II (topo II) to DNA. These compounds have potent cytotoxic activity (IC(50) = 0.9-7.6 nM) against the A2780 human ovarian carcinoma cell line. Hydroxyethylaminoanthraquinones also reported in this paper have similar IC(50) values (0.7-1.7 nM) in the same cell line. Alchemix (ZP281M, 1-(2-[N,N-bis(2-chloroethyl)amino]ethylamino)-4-(2-[N,N-(dimethyl)amino]ethylamino)-5,8-dihydroxy-9,10-anthracenedione), an alkylating anthraquinone, retains excellent antitumor activity in Adriamycin-resistant (2780AD) and cisplatin-resistant (2780/cp70) cell lines in vitro and in vivo. This indicates that Alchemix can evade both P-glycoprotein efflux pump and DNA mismatch repair-mediated resistance. In treated cells, Alchemix was shown to preferentially induce drug-stabilized covalent bound topo IIalpha-DNA complexes over topo IIbeta-DNA complexes.
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PMID:Alchemix: a novel alkylating anthraquinone with potent activity against anthracycline- and cisplatin-resistant ovarian cancer. 1288 32

The anticancer anthracycline compound Adriamycin is a known topoisomerase II inhibitor but is also capable of exerting other cellular consequences. After intercalation, Adriamycin can form covalent adducts with DNA, and the magnitude of these adducts appears to be limited by the cellular availability of formaldehyde. Adducts produced by Adriamycin in the presence of formaldehyde have been well characterized in cell-free systems but not in cells. In this study, we show that when Adriamycin is used in conjunction with the formaldehyde-releasing prodrug AN-9 in IMR-32 tumor cells, this allows the formation of sufficiently high levels of adducts in genomic DNA to enable detection of their DNA sequence specificity for the first time. The 340-bp alpha-satellite EcoRI repeat sequence was isolated from drug-treated cells and digested with lambda-exonuclease to determine adduct sites at which exonuclease digestion was blocked. The Adriamycin adducts were formed predominantly at 5'-GC and GG sequences and unstable with respect to elevated temperatures and extended times at 37 degrees C. The use of three anthracycline derivatives lacking a 3'amino group demonstrated that this amino portion is critical for the formation of anthracycline adducts in cells. The structure of these drug-DNA adducts can therefore be considered to be identical to the Adriamycin adducts, which have been characterized rigorously in cell-free systems by X-ray crystallography, two-dimensional nuclear magnetic resonance, and mass spectrometry.
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PMID:Sequence specificity of adriamycin-DNA adducts in human tumor cells. 1288 39

We have shown previously that the Epstein-Barr virus nuclear antigen-1 (EBNA1) can act as a transforming suppressor in the HER2/neu-overexpressing ovarian cancer cells. In the present study, by using flow cytometric analysis, we demonstrate that EBNA1 could prolong G(2)/M phase and sensitize to Taxol-induced apoptosis in the EBNA1-expressing ovarian cancer cell stable transfectants. In addition, EBNA1 could also significantly increase topoisomerase IIalpha protein expression, indicating that the up-regulation of topoisomerase IIalpha may be one of the mechanisms by which EBNA1 enhances the sensitivity of ovarian cancer cells to topoisomerase II-targeting anticancer drugs, such as VP-16 and Adriamycin. These data suggest that EBNA1 not only prolongs cell cycle at G(2)/M phase and up-regulates topoisomerase IIalpha expression in HER2/neu-overexpressing ovarian cancer cells, but also increases cellular apoptosis through sensitization of cancer cells to topoisomerase II-directing anticancer drugs.
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PMID:EBNA1 may prolong G(2)/M phase and sensitize HER2/neu-overexpressing ovarian cancer cells to both topoisomerase II-targeting and paclitaxel drugs. 1289 73

To investigate the enzyme-inhibitory efficacy and the cytotoxicity of reticulol produced from a strain of Streptoverticillium, we conducted a DNA topoisomerase (Topo) cleavage assay and an in vivo assay using B16F10 melanoma. From the inhibition assay of reticulol for Topo I, which is involved in melanoma metastasis, it was seen that Topo I treated with 45 microM reticulol did not replicate or transcribe DNA by forming supercoiled DNA. In the annexin V/propidium iodide staining assay to investigate the death pattern of B16F10 cells treated with 200 microM reticulol, proliferation of B16F10 cells was inhibited due to necrosis. Furthermore, from the in vivo assay, reticulol combined with Adriamycin (a mixture with retinolol 5 mg/kg and Adriamycin 1 mg/kg) further retarded the tumor growth compared to that in mice treated with Adriamycin alone (1 mg/kg). The survival rate of tumor-bearing mice treated with the mixture was closely associated with its cytotoxicity. Taken together, these results suggested that reticulol inactivates Topo I, which is involved in tumor metastasis, and exhibits excellent cytotoxic efficacy against B16F10 melanoma, when combined with Adriamycin, in a mouse model.
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PMID:Topoisomerase I inactivation by reticulol and its in vivo cytotoxicity against B16F10 melanoma. 1450 38

Adriamycin is one of the most active anticancer drugs but the development of resistance to this drug hampers its efficacy. In an effort to identify novel genes that confer resistance to adriamycin, we introduced a yeast genomic library into Saccharomyces cerevisiae and selected transformants that grew in the presence of a normally toxic concentration of adriamycin. Detailed examination of a plasmid recovered from these transformants revealed that overexpression of the gene for Ssl2p rendered yeast cells resistant to adriamycin. Ssl2p is a protein that is involved in the initiation of transcription and in DNA repair. Overexpression of Ssl2p did not confer resistance to aclarubicin, an anthracycline anticancer drug, which, like adriamycin, is intercalated into DNA. Both adriamycin and aclarubicin inhibit topoisomerase II and, thus, topoisomerase II might not be a major factor in the acquired resistance to adriamycin that results from overexpression of Ssl2p. We tested several other compounds but the only one to which Ssl2p-overexpressing cells were cross-resistant was actinomycin D. Mammalian cells that overexpress P-glycoprotein, which is a transmembrane protein that is involved in the efflux of certain drugs, are resistant to both adriamycin and actinomycin D but not to aclarubicin. However, overexpression of Ssl2p had little or no effect on the intracellular accumulation of adriamycin. Our results suggest that a novel mechanism might be involved in the sensitivity of yeast to both adriamycin and actinomycin D.
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PMID:Overexpression of Ssl2p confers resistance to adriamycin and actinomycin D in Saccharomyces cerevisiae. 1474 13

DA-125, a novel derivative of adriamycin, is known for its anti-cancer activity. In this study, the inhibitory mechanism of DA-125 on topoisomerase was investigated in the simian virus 40 (SV40) replicating CV-1 cell by studying the SV40 DNA replication intermediates and DNA-topoisomerase complexes. DNA-protein complexes that were formed in the drug-treated cells were quantitated by using a glass filter assay. SV40 DNA replication intermediates that were accumulated in the drug-treated CV-1 cell were analyzed in a high resolution gel. DA-125 did not accumulate B-dimers of SV40 DNA replication intermediates which were found in the adriamycin-treated CV-1 cells. DA-125 induced a dose-dependent formation of the DNA-protein complexes, while adriamycin did not. When adriamycin and etoposide (VP16) were added to the SV40-infected cells at the same time, adriamycin blocked the formation of the DNA-protein complexes induced by VP16 in a dose-dependent manner. However, DA-125 blocked the formation of the DNA-protein complexes induced by VP16 up to the maximum level of the DNA-protein complexes that were induced by DA-125 alone. Adriamycin and DA-125 did not inhibit the formation of the DNA-protein complexes that were caused by camptothecin, a known topoisomerase I poison. DA-125 is bifunctional in inhibiting topoisomerase II because it simultaneously has the properties of the topoisomerase II poison and the DNA intercalator. As a topoisomerase II poison, DA-125 alone induced dose-dependent formation of the DNA-protein complexes. However, as a DNA intercalator, it quantitatively inhibited the formation of the DNA-protein complexes induced by a strong topoisomerase II poison VP16. Furthermore considering that the levels of the DNA-protein complex induced by VP16 were decreased by DA-125 in terms of the topoisomerase II poison, we suggest that DA-125 has a higher affinity to the drug-binding sites of DNA than VP16 has.
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PMID:DA-125, a new antitumor agent, inhibits topoisomerase II as topoisomerase poison and DNA intercalator simultaneously. 1496 43

Camptothecin and Adriamycin are clinically important inhibitors for topoisomerase (Topo) I and Topo II, respectively. The ataxia-telangiectasia mutated (ATM) product is essential for ionizing radiation-induced DNA damage responses, but the role of ATM in Topo poisons-induced checkpoints remains unresolved. We found that distinct mechanisms are involved in the activation of different cell cycle checkpoints at different concentrations of Adriamycin and camptothecin. Adriamycin promotes the G(1) checkpoint through activation of the p53-p21(CIP1/WAF1) pathway and decrease of pRb phosphorylation. Phosphorylation of p53(Ser20) after Adriamycin treatment is ATM dependent, but is not required for the full activation of p53. The G(1) checkpoint is dependent on ATM at low doses but not at high doses of Adriamycin. In contrast, the Adriamycin-induced G(2) checkpoint is independent on ATM but sensitive to caffeine. Adriamycin inhibits histone H3(Ser10) phosphorylation through inhibitory phosphorylation of CDC2 at low doses and down-regulation of cyclin B1 at high doses. The camptothecin-induced intra-S checkpoint is partially dependent on ATM, and is associated with inhibitory phosphorylation of cyclin-dependent kinase 2 and reduction of BrdUrd incorporation after mid-S phase. Finally, apoptosis associated with high doses of Adriamycin or camptothecin is not influenced by the absence of ATM. These data indicate that the involvement of ATM following treatment with Topo poisons differs extensively with dosage and for different cell cycle checkpoints.
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PMID:Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms. 1514 Oct 20

Topoisomerase II poisons like Adriamycin (ADR, doxorubicin) are clinically important chemotherapeutic agents. Adriamycin-induced DNA damage checkpoint activates ATM and ATR, which could in turn inhibit the cell cycle engine through either CHK1 or CHK2. In this study, we characterized whether CHK1 or CHK2 is required for Adriamycin-induced checkpoint. We found that both CHK1 and CHK2 were phosphorylated after Adriamycin treatment. Several lines of evidence from dominant-negative mutants, short hairpin RNA (shRNA), and knockout cells indicated that CHK1, but not CHK2, is critical for Adriamycin-induced cell cycle arrest. Disruption of CHK1 function bypassed the checkpoint, as manifested by the increase in CDC25A, activation of CDC2, increase in histone H3 phosphorylation, and reduction in cell survival after Adriamycin treatment. In contrast, CHK2 is dispensable for Adriamycin-induced responses. Finally, we found that CHK1 was upregulated in primary hepatocellular carcinoma (HCC), albeit as an inactive form. The presence of a stockpile of dormant CHK1 in cancer cells may have important implications for treatments like topoisomerase II poisons. Collectively, the available data underscore the pivotal role of CHK1 in checkpoint responses to a variety of stresses.
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PMID:The relative contribution of CHK1 and CHK2 to Adriamycin-induced checkpoint. 1570 69

Doxorubicin (trade name Adriamycin) is a widely used anticancer agent which exhibits good activity against a wide range of tumors. Although the major mode of action appears to be normally as a topoisomerase II poison, it also exhibits a number of other cellular responses, one of which is the ability to form adducts with DNA. For adduct formation doxorubicin must react with cellular formaldehyde to form an activated Schiff base which is then able to form an aminal (N-C-N) linkage to the exocyclic amino group of guanine residues. The mono-adducts form primarily at G of 5'-GCN-3' sequences where the chromophore of the drug is intercalated between the C and N base pair. The structure of the adducts has have been well defined by 2D NMR, mass spectrometry and X-ray crystallography. The formation of these anthracycline adducts in cells grown in culture has been unequivocally demonstrated. The source of formaldehyde in cells can be endogenous, provided by coadministration of prodrugs that release formaldehyde or by prior complexation of anthracyclines with formaldehyde. Since the adducts appear to be more cytotoxic than doxorubicin alone, and also less susceptible to drug-efflux forms of resistance, they offer new approaches to improving the anticancer activity of the anthracyclines.
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PMID:The power and potential of doxorubicin-DNA adducts. 1603 66


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