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)

Anthracycline antibiotics like doxorubicin (DOX) are known to exert their antitumor effects primarily via DNA intercalation and topoisomerase II inhibition. By contrast, the noncross-resistant cytoplasmically localizing DOX analogue, N-benzyladriamycin-14-valerate (AD 198), only weakly binds DNA and does not inhibit topoisomerase II, yet it displays superior antitumor activity, strongly suggesting a distinct cytotoxic mechanism. In recent modeling studies, we reported a structural similarity between AD 198 and commonly accepted ligands for the C1-domain of protein kinase C (PKC), and we hypothesized that the unique biological activity of AD 198 may derive, in part, through this kinase. Consistent with this hypothesis, the present biochemical studies demonstrate that AD 198 competes with [3H]phorbol-12,13-dibutyrate ([3H]PDBu) for binding to phorbol-responsive PKC isoforms, the isolated C1b domain of PKC-delta (delta C1b), and the nonkinase phorbol ester receptor, beta2-chimaerin. In NIH/3T3 cells, AD 198 competitively blocks PKC activation by C1-ligands. Importantly, neither DOX nor N-benzyladriamycin, the principal AD 198 metabolite, inhibits basal or phorbol-stimulated PKC activity or appreciably competes for [3H]PDBu binding. In CEM cells, structure activity studies with 14-acyl congeners indicate that the rapid induction of apoptosis correlates with competition for [3H]PDBu binding, strongly implicating phorbol-binding proteins in drug activity. Collectively, these studies support the conclusion that AD 198 is a C1-ligand and that C1-ligand receptors are selective drug targets. These studies provide the impetus for continuing efforts to understand the molecular basis for the unique biological activity of AD 198 and provide for the design of analogues with improved affinity for C1-domains and potentially greater antitumor activity.
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PMID:Interaction of the novel anthracycline antitumor agent N-benzyladriamycin-14-valerate with the C1-regulatory domain of protein kinase C: structural requirements, isoform specificity, and correlation with drug cytotoxicity. 1247 66

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. Therapeutic interventions for MDS other than allogeneic bone marrow transplantation have been palliative. Because most of the patients are elderly and may not be candidates for ablative transplant conditioning regimens, treatment has focused on supportive care. Recently, several novel biological and chemotherapeutic agents have demonstrated activity in MDS and are being incorporated into the treatment paradigm. These agents are based on specific mechanisms aimed at angiogenesis in the bone marrow, secretion of growth factors and/or their receptors, and modulators in their intracellular pathways. Several agents are in the initial stages of clinical trial, including anti-vascular endothelial growth factor, bevacizumab, receptor tyrosine kinase inhibitors, farnesyl transferase inhibitors, protein kinase C inhibitors, matrix metalloproteinase inhibitors and other agents such as thalidomide and arsenic trioxide. Novel chemotherapeutic agents include topoisomerase inhibitors such as topotecan and rubitecan, and deoxyadenosine analogues such as troxacitabine, tezacitabine, and clofarabine. Prognostic factors predicting response in MDS patients treated with intensive chemotherapy have been identified and include younger age and favorable cytogenetics.
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PMID:Nucleoside analogs and antimetabolite therapies for myelodysplastic syndrome. 1549 95

The cytokine scatter factor/hepatocyte growth factor (HGF/SF) protects epithelial, carcinoma, and other cell types against cytotoxicity and apoptosis induced by DNA-damaging agents such as ionizing radiation and adriamycin (ADR, a topoisomerase IIalpha inhibitor). We investigated the role of nuclear factor kappa B (NF-kappaB) signaling in HGF/SF-mediated protection of human prostate cancer (DU-145) and Madin-Darby canine kidney (MDCK) epithelial cells against ADR. HGF/SF caused the rapid nuclear translocation of the p65 (RelA) subunit of NF-kappaB associated with the transient loss of the inhibitory subunit IkappaB-alpha. Exposure to HGF/SF caused the activation of an NF-kappaB luciferase reporter that was blocked or attenuated by the expression of a mutant 'super-repressor' IkappaB-alpha. Electrophoretic mobility shift assay supershift assays revealed that HGF/SF treatment induced the transient binding of various NF-kappaB family proteins (p65, p50, c-Rel, and RelB) with radiolabeled NF-kappaB-binding oligonucleotides. The HGF/SF-mediated protection of DU-145 and MDCK cells against ADR (demonstrated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays) was abrogated by the IkappaB-alpha super-repressor. The ability of HGF/SF to activate NF-kappaB signaling was dependent on c-Akt --> Pak1 (p21-associated kinase-1) signaling (with Pak1 downstream of c-Akt) and was inhibited by the tumor suppressor PTEN (phosphatase and tensin homolog). Inhibitors of phosphatidylinositol-3'-kinase and Src family kinases significantly inhibited HGF/SF-mediated activation of NF-kappaB, while inhibitors of MEK, protein kinase C, and p70 S6 kinase had a modest effect or no effect on NF-kappaB activity. HGF/SF induced the expression of several known NF-kappaB target genes (cIAP-1 (cellular inhibitor of apoptosis-1), cIAP-2, and TRAF-2 (TNF receptor-associated factor-2)) in an NF-kappaB-dependent manner; HGF/SF blocked the inhibition of expression of these genes by ADR. Experimental manipulation of expression of these genes suggests that they (particularly TRAF-2 and cIAP-2) contribute to the protection against ADR by HGF/SF. These findings suggest that HGF/SF activates NF-kappaB through a c-Akt --> Pak1 signaling pathway that is also dependent on Src, and that NF-kappaB contributes to HGF/SF-mediated protection against ADR.
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PMID:Role of NF-kappaB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. 1568 34

The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Resistance varies. Although regulatory approval may require efficacy in as few as 20% of trial cohorts, a drug may subsequently be used in unselected patients displaying resistance to the treatment. Principal mechanisms may include altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered target enzyme (e.g. mutated topoisomerase II), decreased drug activation, increased drug degradation due to altered expression of drug-metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptose as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance mainly involve the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors and, in specific instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in abrogating or delaying onset of resistance. Gene knockout using antisense molecules may be another effective way of blocking drug resistance genes. Conversely, drug resistance may also be used to good purpose by transplanting retrovirally transformed CD34 cells expressing the MDR gene to protect the bone marrow during high-dose chemotherapy.
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PMID:Mechanisms of drug resistance in cancer chemotherapy. 1610 12

Epidermal growth factor receptor (EGFR) overactivity plays a significant role in colon cancer biology and has been associated with poor clinical prognosis. Early clinical trials reported efficacy of receptor-targeted compounds, including modulation of clinical irinotecan resistance. We investigated the effects of the EGFR tyrosine kinase inhibitor gefitinib on cellular determinants of irinotecan resistance in human colon cancer cells. At non-cytotoxic concentrations, gefitinib sensitized colon cancer cells to SN-38, the active metabolite of irinotecan. Gefitinib increased the SN-38-mediated induction of protein-linked DNA single-strand breaks in a dose-dependent manner, with no alteration of topoisomerase (Topo) I protein expression or enzymatic activity. Whereas Topo IIbeta protein expression was not affected by gefitinib, significant time- and concentration-dependent downregulation of Topo IIalpha protein and inhibition of its enzymatic function were observed, corresponding to a G1 phase cell cycle arrest. Gefitinib significantly inhibited EGFR-associated signaling molecules, including phospho-mitogen-activated protein kinase or protein kinase C, which may account for decreases in proliferation or topoisomerase activity, respectively. Although a dose-dependent decrease of the BCRP/MXR/ABCP half-transporter was observed under gefitinib, cellular pharmacokinetics revealed no significant differences in accumulation or retention of the active SN-38 lactone using reverse-phase HPLC analysis. This study delineates mechanisms that may contribute to the synergism observed between irinotecan and EGFR inhibitors.
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PMID:The epidermal growth factor receptor tyrosine kinase inhibitor gefitinib sensitizes colon cancer cells to irinotecan. 1622 52

Enhanced cytotoxicity of etoposide by wortmannin, an inhibitor of enzymes holding a phosphatidylinositol 3-kinase domain, was investigated in eight cell lines proficient or deficient for DNA double-strand break repair. Wortmannin stimulated the decatenating activity of topoisomerase II, promoted etoposide-induced accumulation of DNA double-strand breaks, shifted the specificity for cell killing by etoposide from the S to G1 phase of the cell cycle, and potentiated the cytotoxicity of etoposide through two mechanisms. (a) Sensitization to high, micromolar amounts of etoposide required integrity of the nonhomologous end-joining repair pathway. (b) Wortmannin dramatically increased the susceptibility to low, submicromolar amounts of etoposide in a large fraction of the cell population irrespective of the status of ATM, Ku86, and DNA-PKCS. It is shown that this process correlates depression of phosphatidylinositol 3-kinase-dependent phosphorylation of the atypical, zeta isoform of protein kinase C (PKCzeta). Stable expression of a dominant-negative, kinase-dead mutant of PKCzeta in a tumor cell line reproduced the hypersensitivity pattern induced by wortmannin. The results are consistent with up-regulation of the topoisomerase II activity in relation to inactivation of PKCzeta and indicate that PKCzeta may be a useful target to improve the efficiency of topoisomerase II poisons at low concentration.
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PMID:A role for PKCzeta in potentiation of the topoisomerase II activity and etoposide cytotoxicity by wortmannin. 1622 94

Topoisomerase II plays an essential role in the segregation of chromosomes during cell division. It is also a major component of the nuclear matrix. Proteins that interact with and regulate this essential enzyme are of great interest. To investigate the role of proteins interacting with the N-terminal domain of the Saccharomyces cerevisiae topoisomerase II, we used a yeast two-hybrid protein interaction screen. We identified an interaction between the catalytic domain of the yeast protein kinase 1 enzyme (Pkc1) and the N-terminal domain of the S. cerevisiae topoisomerase II. The S. cerevisiae Pkc1 is the homologue of the mammalian calcium dependent PKC.
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PMID:The identification of a functional interaction between PKC and topoisomerase II. 1636 7

Unlike nuclear-targeted anthracyclines, the extranuclear-targeted doxorubicin congener, N-benzyladriamycin-14-valerate (AD 198), does not interfere with normal topoisomerase II activity, but binds to the C1b regulatory domain of conventional and novel isoforms of protein kinase C (PKC). The resulting interaction leads to enzyme activation and rapid apoptosis in a variety of mammalian cell lines through a pathway involving mitochondrial events such as membrane depolarization (Deltapsim) and cytochrome c release. Unlike other triggers of apoptosis, AD 198-mediated apoptosis is unimpeded by the expression of Bcl-2 and Bcl-XL. We have further examined AD 198-induced apoptosis in 32D.3 mouse myeloid cells to determine how the anti-apoptotic effects of Bcl-2 are circumvented. The PKC-delta inhibitor, rottlerin, and transfection with a transdominant-negative PKC-delta expression vector both inhibit AD 198 cytotoxicity through inhibition of Deltapsim and cytochrome c release. While the pan-caspase inhibitor Z-VAD-FMK blocks AD 198-induced PKC-delta cleavage, however, it does not inhibit Deltapsim and cytochrome c release, indicating that AD 198 induces PKC-delta holoenzyme activation to achieve apoptotic mitochondrial effects. AD 198-mediated Deltapsim and cytochrome c release are also unaffected by cellular treatment with either the mitochondrial permeability transition pore complex (PTPC) inhibitor cyclosporin A or the Ca chelators EGTA and BAPTA-AM. These results suggest that AD 198 activates PKC-delta holoenzyme, resulting in Deltapsim and cytochrome c release through a mechanism that is independent of both PTPC activation and Ca flux across the mitochondria. PTPC-independent mitochondrial activation by AD 198 is consistent with the inability of Bcl-2 and Bcl-XL expression to block AD 198-induced apoptosis.
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PMID:N-benzyladriamycin-14-valerate (AD 198) activates protein kinase C-delta holoenzyme to trigger mitochondrial depolarization and cytochrome c release independently of permeability transition pore opening and Ca2+ influx. 1670 5

Caspase-2 exists as two main isoforms: the caspase-2L long isoform, which is pro-apoptotic, and the caspase-2S short isoform, which may be anti-apoptotic. Topoisomerase inhibitors drive inclusion of exon 9, specific for Casp-2S mRNA, and lower Casp-2L [corrected] mRNA and protein. With cell lines engineered to express various PKC isoforms, we demonstrate that PKC zeta, but not PKCalpha, positively regulates Casp-2S mRNA assembly triggered by topoisomerase inhibitors. In addition, exon 9 inclusion is lowered in mitosis but increased in the G1/S phase. Hence, the control of caspase-2 exon 9 inclusion by topoisomerase inhibitors depends on phosphorylation and/or dephosphorylation events, and on the cell cycle phase.
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PMID:PKC zeta controls DNA topoisomerase-dependent human caspase-2 pre-mRNA splicing. 1816 55

The heterocyclic carboxyborane amines were found to be potent cytotoxic agents in the murine L1210 lymphoid leukemia and human HeLa suspended carcinoma cells. These agents were observed to inhibit HeLa DNA topoisomerase II activity ~ 200 muM and L1210 topoisomerase II activity >/= 100 muM. These agents did not cause DNA protein linked breaks themselves, but upon incubation for 14-24 hr did enhance the ability of VP-16 to cause cleavable complexes. The heterocyclic amineboranes inhibited DNA synthesis and caused DNA strand scission. They were additive with VP-16 in affording these results as well as inhibiting colony growth of L1210 cells after co-incubation for 1 hr. The agents inhibited in vitro PKC phosphorylation of both L1210 lymphoid leukemia and human topoisomerase II enzyme.
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PMID:Cytotoxic action of carboxyborane heterocyclic amine adducts. 1847 92


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