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

---

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

Epithelial ovarian carcinoma is worldwide the sixth most common female cancer, and this malignancy carries the highest mortality among all gynecological cancers. The high mortality is due mostly to the fact that the tumor is frequently diagnosed late, in advanced stage, as the early disease is often asymptomatic and no effective screening methods are available. The most important prognostic factors in ovarian carcinoma are the stage, size of residual tumor following surgery, presence of ascites, age and the general condition of the patient, tumor histology, and, in patients with early disease, also the grade of the tumor. Large number of studies on prognostic and predictive factors in epithelial ovarian carcinoma has been published, often with contradictory results. The most intensely studied prognostic factors are those for expression of hormonal receptors, for tumor proliferation activity (mainly by antigen Ki-67 and topoisomerase IIalpha), the markers of apoptosis (p53, p21, mdm2, bcl-2 and other proteins), or other oncoproteins (particularly HER-2/neu).
...
PMID:Contribution of immunohistochemistry in prognostic assessment of epithelial ovarian carcinoma --review of the literature I. 1711 4

D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is herein identified as a novel antineoplastic agent with a broad spectrum of antitumoral activity against several human cancer cells and an IC(50) value in the nanomolar range. The IC(50) values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were >10 mumol/L. D-501036 exhibited no cross-resistance with vincristine- and paclitaxel-resistant cell lines, whereas a low level of resistance toward the etoposide-resistant KB variant was observed. Cell cycle analysis established that D-501036 treatment resulted in a dose-dependent accumulation in S phase with concomitant loss of both the G(0)-G(1) and G(2)-M phase in both Hep 3B and A-498 cells. Pulsed-field gel electrophoresis showed D-501036-induced, concentration-dependent DNA breaks in both Hep 3B and A-498 cells. These breaks did not involve interference with either topoisomerase-I and topoisomerase-II function or DNA binding. Rapid reactive oxygen species production and formation of Se-DNA adducts were evident following exposure of cells to D-501036, indicating that D-501036-mediated DNA breaks were attributable to the induction of reactive oxygen species and DNA adduct formation. Moreover, D-501036-induced DNA damage activated ataxia telangiectasia-mutated nuclear protein kinase, leading to hyperphosphorylation of Chk1, Chk2, and p53, decreased expression of CDC25A, and up-regulation of p21(WAF1) in both p53-proficient and p53-deficient cells. Collectively, the results indicate that D-501036-induced cell death was associated with DNA damage-mediated induction of ataxia telangiectasia-mutated activation, and p53-dependent and -independent apoptosis pathways. Notably, D-501036 shows potent activity against the growth of xenograft tumors of human renal carcinoma A-498 cells. Thus, D-501036 is a promising anticancer compound that has strong potential for the management of human cancers.
...
PMID:D-501036, a novel selenophene-based triheterocycle derivative, exhibits potent in vitro and in vivo antitumoral activity which involves DNA damage and ataxia telangiectasia-mutated nuclear protein kinase activation. 1723 79

Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates within tumors in vivo and protects tumor cells against cytotoxicity and apoptosis due to DNA damaging agents in vitro. Previous studies have established that SF-mediated cell protection involves antiapoptotic signaling from its receptor (c-Met) to PI3 kinase --> c-Akt --> Pak1 (p21-activated kinase -1) --> NF-kappaB (nuclear factor-kappa B). Here, we found that Ras proteins (H-Ras and R-Ras) enhance SF-mediated activation of NF-kappaB and protection of DU-145 and MDCK (Madin-Darby canine kidney) cells against the topoisomerase IIalpha inhibitor adriamycin. Studies of Ras effector loop mutants and their downstream effectors suggest that Ras/PI3 kinase and Ras/Raf1 pathways contribute to SF stimulation of NF-kappaB signaling and cell protection. Further studies revealed that Raf1 positively regulates the ability of SF to stimulate NF-kappaB activity and cell protection. The ability of Raf1 to stimulate NF-kappaB activity was not due to the classical Raf1 --> MEK1/2 --> ERK1/2 pathway. However, we found that a MEK3/6 --> p38 pathway contributes to SF-mediated activation of NF-kappaB. In contrast, RalA, a target of the Ras/RalGDS pathway negatively regulated the ability of SF to stimulate NF-kappaB activity and cell protection. Ras, Raf1 and RalA modulate SF stimulation of NF-kappaB activity, in part, by regulating IkappaB kinase (IKK)-beta kinase activity. These findings suggest that Ras/Raf1/RalA pathways may converge to modulate NF-kappaB activation and SF-mediated survival signaling at the IKK complex and/or a kinase upstream of this complex.
...
PMID:Ras effector pathways modulate scatter factor-stimulated NF-kappaB signaling and protection against DNA damage. 1729 51

Using high-throughput screening with small-molecule libraries, we identified a compound, KCG165 [(2-(3-(2-(pyrrolidin-1-yl)ethoxy)-1,10b-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one)], which strongly activated p53-mediated transcriptional activity. KCG165-induced phosphorylations of p53 at Ser(6), Ser(15), and Ser(20)(,) which are all key residues involved in the activation and stabilization of p53. Consistent with these findings, KCG165 increased level of p53 protein and led to the accumulation of transcriptionally active p53 in the nucleus with the increased occupancy of p53 in the endogenous promoter region of its downstream target gene, p21(WAF1/CIP). Notably, KCG165-induced p53-dependent apoptosis in cancer cells. Furthermore, we suggested topoisomerase II as the molecular target of KCG165. Together, these results indicate that KCG165 may have potential applications as an antitumor agent.
...
PMID:Novel small molecule induces p53-dependent apoptosis in human colon cancer cells. 1750 29

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.
...
PMID:Response of cell cycle/stress-related protein expression and DNA damage upon treatment of CaCo2 cells with anthocyanins. 1805 7

The protein tyrosine kinase inhibitor, genistein, has been reported to inhibit proliferation and to induce cell death in various non-solid and solid cancer cell lines. Herein, we examined the effects of genistein in several human malignant glioma cell lines. We found that genistein inhibited the proliferation of LN-18, LNT-229, LN-308 and T98G cells at EC50 concentrations of 25-80 microM (72 h of exposure). The growth of a non-neoplastic immortalized human astrocyte cell line, SV-FHAS, was inhibited at similar concentrations. There was a reduction in [3H]-methylthymidine incorporation and a moderate lactate dehydrogenase release as a sign of cell death in genistein-treated glioma cells. Electron microscopy showed morphological changes with mitochondrial swelling and apoptosis in glioma cells treated with high concentrations of genistein. Genistein-induced cytotoxicity was associated with an increased DNA/topoisomerase II complex formation. Furthermore, genistein induced cell cycle arrest in G2/M. There was an increase in the p53 and p21 levels in response to genistein. However, there was no difference in genistein sensitivity between p21-deficient colon carcinoma cells and isogenic control cells. Genistein-induced cell death in LN-18 and LNT-229 was unaffected by the ectopic expression of the preferential caspase 1/8 inhibitor, crm-A, or co-exposure to the pan-specific pseudosubstrate caspase inhibitor, zVAD-fmk. The ectopic expression of the anti-apoptotic BCL-2 protein attenuated the cytotoxic effects of genistein. Moreover, the ectopic expression of temperature-sensitive p53V135A, which acts as a dominant-negative p53 mutant at 38.5 degrees C but assumes p53 wild-type properties at 32.5 degrees C, in LN-18 or LNT-229 cells, had no effect on genistein cytotoxicity at either temperature. Genistein did not act in synergy with CD95 ligand-induced apoptosis or various cancer chemotherapy drugs in cytotoxic or clonogenic cell death assays. Thus, genistein-like protein kinase inhibitors are promising agents for the experimental treatment of malignant gliomas.
...
PMID:The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines. 1835 97

The Mre11 complex promotes DNA double-strand break repair and regulates DNA damage signaling via activation of the ataxia-telangiectasia mutated (ATM) kinase. The hypermorphic Rad50(S) allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing Rad50(S) experience constitutive ATM activation, which leads to precipitous apoptotic attrition in hematopoietic cells. In this study, we show that ATM activation by the Rad50S-containing Mre11 complex enhances the proliferation of LSK cells, a population consisting of hematopoietic stem cells and multipotent progenitor cells. In Rad50(S/S) mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when Rad50(S/S) is combined with mutations that alter either LSK cell quiescence (myeloid elf-1-like factor/ELF4-deficient mice) or hematopoietic differentiation (p21- and p27-deficient mice), indicating that the LSK population is a primary target of Rad50(S) pathology. We show that cells from Rad50(S/S) mice are hypersensitive to camptothecin, a topoisomerase I inhibitor that causes DNA damage primarily during DNA replication. On this basis, we propose that apoptotic attrition of Rad50(S/S) hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in Rad50(S/S) mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentially oncogenic lesions in Rad50(S/S) mice. These data provide compelling evidence that the Mre11 complex plays a role in the metabolism of topoisomerase lesions in mammals, and further suggest that such lesions can accumulate in primitive hematopoietic cells and confer significant oncogenic potential.
...
PMID:DNA damage signaling in hematopoietic cells: a role for Mre11 complex repair of topoisomerase lesions. 1838 24

Ochratoxin A (OTA) is a potent renal carcinogen, but little is known regarding the mechanism of OTA carcinogenicity. Early histopathological alterations induced by OTA in rat kidney include single cell death, stimulation of cell proliferation and prominent karyomegaly indicative of blocked nuclear division during mitosis. Based on these observations, it has been suggested that disruption of mitosis by OTA may be the principal cause of cell death and subsequent trigger for cell proliferation to compensate for cell loss. To gain further insight into the molecular mechanism of OTA toxicity, we used targeted quantitative real-time polymerase chain reaction arrays to investigate the expression of genes involved in cell cycle control and mitosis in kidneys of male F344 rats treated with 0, 21, 70 and 210 microg/kg body wt OTA for up to 90 days. Treatment with OTA resulted in overexpression of key regulators of mitosis, including the mitotic protein kinases Polo-like kinase 1, Aurora B and cyclin-dependent kinase 1 (Cdk1Cdc2), several cyclins and cyclin-dependent kinase inhibitors, topoisomerase II and survivin. Immunohistochemical analysis confirmed upregulation of Cdk1, p21(WAF1/CIP1), topoisomerase II and survivin in S3 proximal tubule cells, from which OTA-induced tumors in rats arise, and demonstrated increased phosphorylation of histone H3, a target of Aurora B. Importantly, many of the genes found to be deregulated in response to OTA have been linked to chromosomal instability and malignant transformation, supporting the hypothesis that aberrant mitosis, resulting in blocked or asymmetric cell division, accompanied by an increased risk of aneuploidy acquisition, may play a critical role in OTA carcinogenicity.
...
PMID:Modulation of key regulators of mitosis linked to chromosomal instability is an early event in ochratoxin A carcinogenicity. 1923 4

Mdm2 inhibitors represent a promising class of p53 activating compounds that may be useful in cancer treatment and prevention. However, the consequences of pharmacological p53 activation are not entirely clear. We observed that Nutlin-3 triggered a DNA damage response in azoxymethane-induced mouse AJ02-NM(0) colon cancer cells, characterized by the phosphorylation of H2AX (at Ser-139) and p53 (at Ser-15). The DNA damage response was highest in cells showing robust p53 stabilization, it could be triggered by the active but not the inactive Nutlin-3 enantiomer, and it was also activated by another pharmacological Mdm2 inhibitor (Caylin-1). Quantification of gamma H2AX-positive cells following Nutlin-3 exposure showed that approximately 17% of cells in late S and G2/M were mounting a DNA damage response (compared to a approximately 50% response to 5-fluorouracil). Nutlin-3 treatment caused the formation of double-strand DNA strand breaks, promoted the formation of micronuclei, accentuated strand breakage induced by doxorubicin and sensitized the mouse colon cancer cells to DNA break-inducing topoisomerase II inhibitors. Although the HCT116 colon cancer cells did not mount a significant DNA damage response following Nutlin-3 treatment, Nutlin-3 enhanced the DNA damage response to the nucleotide synthesis inhibitor hydroxyurea in a p53-dependent manner. Finally, p21 deletion also sensitized HCT116 cells to the Nutlin-3-induced DNA damage response, suggesting that cell cycle checkpoint abnormalities may promote this response. We propose that p53 activation by Mdm2 inhibitors can result in the slowing of double-stranded DNA repair. Although this effect may suppress illegitimate homologous recombination repair, it may also increase the risk of clastogenic events.
...
PMID:DNA damage response to the Mdm2 inhibitor nutlin-3. 1978 89

The possibility of synergism between the topoisomerase inhibition by coralyne and its DNA photonicking properties being used to kill cancer cells was explored. Compared with coralyne alone, the CUVA treatment dramatically enhanced DNA damage and apoptosis in cells. Despite causing an increased p53 expression, the CUVA treatment led to p53-independent apoptosis, causing almost similar cell death in wild-type, p53 mutant, and p53-silenced tumor cells. Expression of the p53-regulated downstream proteins like p21, and DNA-damage-dependent p53 phosphorylation at serine-15 residue also was not elicited by the CUVA treatment, at a low coralyne concentration. Instead, it led to an immediate activation of the Chk2-mediated S-phase arrest, despite activating PARP protein for DNA repair. The S-phase arrest subsequently ensures apoptosis through activation of caspases-3 and -9, the latter being reflected from the results with a specific caspase-9 inhibitor. Abrogation of Chk2 activity by shRNA or by using ATM-specific inhibitor (ATMi) led to a defective S-phase checkpoint and further augmentation in apoptosis. However, at a high coralyne concentration, the CUVA-induced apoptosis followed multiple and independent pathways, involving several caspases. The CUVA treatment may represent a novel mechanism-based protocol for increasing the efficacy of coralyne in inducing apoptosis in both p53 wild-type and mutant tumor cells.
...
PMID:Topoisomerase inhibitor coralyne photosensitizes DNA, leading to elicitation of Chk2-dependent S-phase checkpoint and p53-independent apoptosis in cancer cells. 1992 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---