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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drug-treated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.
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PMID:Antitumor efficacy of edotecarin as a single agent and in combination with chemotherapy agents in a xenograft model. 1667 81

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by ionizing radiation and topoisomerase II poisons, such as etoposide and doxorubicin. A major pathway for the repair of DSB is nonhomologous end joining, which requires DNA-dependent protein kinase (DNA-PK) activity. We investigated the therapeutic use of a potent, specific DNA-PK inhibitor (NU7441) in models of human cancer. We measured chemosensitization by NU7441 of topoisomerase II poisons and radiosensitization in cells deficient and proficient in DNA-PK(CS) (V3 and V3-YAC) and p53 wild type (LoVo) and p53 mutant (SW620) human colon cancer cell lines by clonogenic survival assay. Effects of NU7441 on DSB repair and cell cycle arrest were measured by gammaH2AX foci and flow cytometry. Tissue distribution of NU7441 and potentiation of etoposide activity were determined in mice bearing SW620 tumors. NU7441 increased the cytotoxicity of ionizing radiation and etoposide in SW620, LoVo, and V3-YAC cells but not in V3 cells, confirming that potentiation was due to DNA-PK inhibition. NU7441 substantially retarded the repair of ionizing radiation-induced and etoposide-induced DSB. NU7441 appreciably increased G(2)-M accumulation induced by ionizing radiation, etoposide, and doxorubicin in both SW620 and LoVo cells. In mice bearing SW620 xenografts, NU7441 concentrations in the tumor necessary for chemopotentiation in vitro were maintained for at least 4 hours at nontoxic doses. NU7441 increased etoposide-induced tumor growth delay 2-fold without exacerbating etoposide toxicity to unacceptable levels. In conclusion, NU7441 shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use.
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PMID:Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. 1670 62

The substituted chloroisoquinolinediones and pyrido[3,4-b]phenazinediones were synthesized, and the cytotoxic activity and topoisomerase II inhibitory activity of the prepared compounds were evaluated. Chloroisoquinolinediones have been prepared by the reported method employing 6,7-dichloroisoquinoline-5,8-dione. The cyclization to pyrido[3,4-b]phenazinediones was achieved by adding the aqueous sodium azide solution to the dimethylformamide solution of corresponding chloroisoquinoline-5,8-dione. The cytotoxicity of the synthesized compounds was evaluated by a SRB (Sulforhodamine B) assay against various cancer cell lines such as A549 (human lung cancer cell line), SNU-638 (human stomach cancer cell), Col2 (human colon cancer cell line), HT1080 (human fibrosarcoma cell line), and HL-60 (human leukemia cell line). Almost all the synthesized pyrido[3,4-b]phenazinediones showed greater cytotoxic potential than ellipticine (IC(50)=1.82-5.97 microM). In general, the cytotoxicity of the pyrido[3,4-b]phenazinediones was higher than that of the corresponding chloroisoquinolinediones. The caco-2 cell permeability of selected compounds was 0.62 x 10(-6)-35.3 x 10(-6)cm/s. The difference in cytotoxic activity among tested compounds was correlated with the difference in permeability to some degree. To further investigate the cytotoxic mechanism, the topoisomerase II inhibitory activity of the synthesized compounds was estimated by a plasmid cleavage assay. Most of compounds showed the topoisomerase II inhibitory activity (28-100%) at 200 microM. IC(50) values for the most active compound 6a were 0.082 microM. However, the compounds were inactive for DNA relaxation by topoisomerase I at 200 microM.
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PMID:Synthesis of 6-chloroisoquinoline-5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity. 1703 25

SN38 is the active metabolite of the anti-cancer agent irinotecan (CPT-11) and is a potent inhibitor of topoisomerase-I (topo-I), leading to DNA strand breaks and eventually cell death. The pyrimidine analog trifluorothymidine (TFT) is part of the anti-cancer drug formulation TAS-102, which was developed to enhance the bioavailability of TFT in vivo, and is currently being evaluated as an oral chemotherapeutic agent in phase I clinical studies. In this study, the combined cytotoxic effects of dual-targeted TFT with SN38 were investigated in a panel of human colon cancer cell lines (WiDr, H630, Colo320, SNU-C4, SW1116). We used different drug combination treatment schedules of SN38 with TFT, and possible synergism was evaluated using median drug effect analysis resulting in combination indexes (CI), in which CI<0.9 indicates synergism, CI=0.9-1.1 indicates additivity and CI>1.1 indicates antagonism. Drug target analysis was performed to investigate the effect of TFT on SN38-induced DNA damage, cell cycle delay and apoptosis. Simultaneous exposure to SN38 in combination with TFT was not more than additive, whereas pre-incubation with TFT resulted in synergism with SN38 (CI=0.3-0.6). Only for Colo320 synergism could be induced for both simultaneous and sequential drug combinations. SN38 and TFT induced most DNA damage in H630 and Colo320 cells, which was increased in combination. TFT pre-incubation further enhanced SN38-induced DNA strand breaks in H630 and Colo320 (>20%), which was most pronounced in H630 cells (p<0.01). Exposure to SN38 alone induced a clear cell cycle G2M-phase arrest and pre-incubation with TFT enhanced this effect in WiDr and H630 (p<0.05). Both drugs induced significant apoptosis; SN38-induced apoptosis increased significantly in the presence of TFT (p<0.01), either when added simultaneously (about 3-fold) or at pre-incubation (about 2-fold). Topo-I protein levels varied among the cell lines and TFT hardly affected these. In conclusion, TFT pre-incubation can enhance SN38-induced cytotoxicity to colon cancer cells resulting in synergism between the drugs, thereby increasing DNA damage and apoptosis induction.
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PMID:Irinotecan-induced cytotoxicity to colon cancer cells in vitro is stimulated by pre-incubation with trifluorothymidine. 1704 27

Twelve analogs of makaluvamines have been synthesized. These compounds were evaluated for their ability to inhibit the enzyme topoisomerase II. Five compounds were shown to inhibit topoisomerase catalytic activity comparable to two known topoisomerase II targeting control drugs, etoposide and m-AMSA. Their cytotoxicity against human colon cancer cell line HCT-116 and human breast cancer cell lines MCF-7 and MDA-MB-468 has been evaluated. Four makaluvamine analogs exhibited better IC(50) values against HCT-116 as compared to control drug etoposide. One analog exhibited better IC(50) value against HCT-116 as compared to m-AMSA. All 12 of the makaluvamine analogs exhibited better IC(50) values against MCF-7 and MDA-MB-468 as compared to etoposide as well as m-AMSA.
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PMID:Analogs of the marine alkaloid makaluvamines: synthesis, topoisomerase II inhibition, and anticancer activity. 1736 22

The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin-formaldehyde conjugate. The IC(50) for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA cross-linking agents than with growth inhibition by doxorubicin. Doxorubicin induces G2/M arrest in HCT-116 colon cancer cells and HL-60 leukemia cells through a well-documented topoisomerase II dependent mechanism. Doxazolidine fails to induce a G2/M arrest in HCT-116 cells but induces apoptosis 4-fold better than doxorubicin. The IC(50) for doxazolidine growth inhibition of HL-60/MX2 cells, a topoisomerase II deficient derivative of HL-60 cells, is 1420-fold lower than the IC(50) for doxorubicin, and doxazolidine induces apoptosis 15-fold better. Further, doxazolidine has little effect in a topoisomerase II activity assay. These data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms and doxazolidine cytotoxicity is topoisomerase II independent.
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PMID:Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism. 1769 16

Anthocyanins are a class of flavonoids, widely spread throughout the plant kingdom, exhibiting important antioxidant and anti-inflammatory actions as well as chemotherapeutic effects; nonetheless, little is known about the molecular mechanisms by which these activities are exerted. The present study is aimed at investigating molecular mechanisms involved in the chemotherapeutic effects induced by both cyanidin-3-O-beta glucopyranoside (CY3G) and its aglycon form, cyanidin chloride (CY), in human colon cancer cells (CaCo2). The effect on cell growth, reactive oxygen species (ROS) formation and cell cycle/stress proteins modification, including ataxia teleangectasia mutated protein (ATM), p53, p21, 8-oxoguanine DNA glycosylase (OGG1), 70 kDa heat shock protein (HSP70) and topoisomerase IIbeta, as well as on DNA fragmentation, was determined. CY and CY3G treatment affect cell growth and cell proliferation, this latter in a moderately dose-dependent way. Interestingly, ROS level is decreased by any concentration of CY and, only at the lowest concentration, by CY3G. Moreover, the two molecules exert their activities increasing ATM, topoisomerase II, HSP70 and p53 expression. The analysis of DNA fragmentation by Comet assay evidences: (1) a dose-dependent increase in DNA damage only after treatment with CY3G; (2) a more evident trend in the DNA fragmentation when the treatment is performed on agarose embedded cells (cellular atypical Comet); (3) a highly dose-dependent DNA fragmentation induced by CY when the treatment is carried out on agarose embedded naked DNA (acellular atypical Comet). The present findings substantiate a possible chemotherapeutic role of anthocyanins and suggest that CY and CY3G act on CaCo2 by different mechanisms, respectively, ROS-dependent and ROS-independent.
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PMID:Response of cell cycle/stress-related protein expression and DNA damage upon treatment of CaCo2 cells with anthocyanins. 1805 7

Physiological cell conditions such as glucose deprivation and hypoxia play roles in the development of drug resistance in solid tumors. These tumor-specific conditions cause decreased expression of DNA topoisomerase IIalpha, rendering cells resistant to topo II target drugs such as etoposide. Thus, targeting tumor-specific conditions such as a low glucose environment may be a novel strategy in the development of anticancer drugs. On this basis, we established a novel screening program for anticancer agents with preferential cytotoxic activity in cancer cells under glucose-deprived conditions. We recently isolated an active compound, AA-98, from Streptomyces sp. AA030098 that can prevent stress-induced etoposide resistance in vitro. Furthermore, LC-MS and various NMR spectroscopic methods identified AA-98 as mithramycin, which belongs to the aureolic acid group of antitumor compounds. We found that mithramycin prevents the etoposide resistance that is induced by glucose deprivation. The etoposide-chemosensitive action of mithramycin was just dependent on strict low glucose conditions, and resulted in the selective cell death of etoposide-resistant HT-29 human colon cancer cells.
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PMID:Mithramycin inhibits etoposide resistance in glucose-deprived HT-29 human colon carcinoma cells. 1809 71

Flavone and camptothecin were both shown to potently induce apoptosis in HT-29 human colon cancer cells. Whereas camptothecin acts on the basis of topoisomerase-I inhibition, flavone appears to burst mitochondrial production of reactive oxygen species by increasing respiratory chain activity. In our study, we searched for similarities and differences in the proteome response of HT-29 cells when treated with the two different compounds. The accessible proteome of HT-29 cells was separated subsequent to the exposure to flavone or camptothecin by 2D-polyacrylamide-gel electrophoresis using pH-gradients between 4 and 7 and 6 and 11 in the first dimension and proteins with changed expression level were identified by peptide mass fingerprints of tryptic digests of the protein spots. Whereas there was a high congruence with regard to the identities of regulated proteins and their grade of regulation, a number of spots changed specifically only in response to either flavone or camptothecin. Nuclear envelope proteins were specifically increased by camptothecin indicating the intervention of this drug with cell division processes. Increased levels of coproporphyrinogen III oxidase, involved in cytochrome synthesis, and ubiquinol-cytochrome-c reductase suggest adaptations to flavone in order to enable a higher substrate flux through the respiratory chain. In conclusion, HT-29 cells respond to camptothecin and flavone with regulations of many proteins in a similar manner suggesting those alterations to be caused by apoptosis induction. Some protein regulations, however, were specific for each compound and point to the mechanism of their action.
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PMID:Proteome response in HT-29 human colorectal cancer cells to two apoptosis-inducing compounds with different mode of action. 1821 53

In the present investigation, the cytotoxic, hydroxyl radical scavenging and topoisomerase inhibition activities of Tabernaemontana divaricata (Apocynaceae) were evaluated. The extracts from leaves of the plant were prepared with different solvents viz. chloroform, methanol, ethyl acetate and hexane. In, in vitro cytotoxicity assay, with cell lines viz HCT-15 (Colon), HT-29 (Colon), 502713 (Colon), MCF-7 (Breast), PC- 3 (Prostrate), it was observed that the ethyl acetate extract was effective against only one colon cell line (502713) at the lowest dose i.e. 10 micro g/ml, whereas the chloroform extract was effective against all the three colon cancer cell lines, at 30 microg/ ml. In order to evaluate the mechanism of cytotoxicity of these extracts, they were assessed for their ability to scavenge hydroxyl radicals in plasmid nicking assay with pBR322. It was observed that all the extracts effectively inhibited the unwinding of supercoiled DNA except hexane extract, which showed the least effect. Since the expression of topo enzymes is linked with cell proliferation so the extracts were also checked for topo I and topo II inhibitory activities. It was noticed that ethyl acetate extract selectively showed inhibition of topo II in topoisomerase II relaxation assay.
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PMID:Studies on cytotoxic, hydroxyl radical scavenging and topoisomerase inhibitory activities of extracts of Tabernaemontana divaricata (L.) R.Br. ex Roem. and Schult. 1857 13


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