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)

Topoisomerase II is a target for a number of chemotherapeutic agents used in the treatment of cancer. Its essential physiological role in modifying the topology of DNA involves the generation of transient double-strand breaks. Anti-cancer drugs, such as mitoxantrone, that target this enzyme interrupt its catalytic cycle and give rise to persistent double strand breaks, which may be lethal to a cell. We investigated the role of such lesions in signaling the activation of the transcription factor nuclear factor kappaB (NFkappaB) by this drug. Mitoxantrone activated NFkappaB and stimulated IkappaBalpha degradation in the promyelocytic leukemia cell line HL60 but not in the variant cells, HL60/MX2 cells, which lack the beta isoform of topoisomerase II and express a truncated alpha isoform that results in an altered subcellular distribution. Treatment of sensitive HL60 cells with mitoxantrone led to a depletion of both isoforms, suggesting the stabilization of transient DNA-topoisomerase II complexes. This depletion was absent in the variant cells, HL60/MX2. Activation of caspase 3 by mitoxantrone was also impaired in the HL60/MX2 cells. NFkappaB activation in response to tumor necrosis factor and bleomycin, the latter causing topoisomerase II-independent DNA damage, was intact in both cell lines. An inhibitor rather than a poison of topoisomerase II, Imperial Cancer Research Fund 187 (ICRF 187) the mechanism of which does not involve the generation of double strand breaks, did not activate NFkappaB, nor did it induce apoptosis in parental HL60 cells. However, ICRF 187 protected against IkappaB degradation in parental HL60 cells in response to mitoxantrone. This protection was also shown with another topoisomerase II inhibitor, merbarone, which is structurally and functionally distinct from ICRF 187. Their effects were specific, as neither protected against tumor necrosis factor-stimulated IkappaB degradation. The poisoning of topoiso- merase II with resultant DNA damage is therefore a critical signal for NFkappaB activation.
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PMID:Topoisomerase II is required for mitoxantrone to signal nuclear factor kappa B activation in HL60 cells. 1094 Mar 16

In the Karnell Cancer Center Grand Rounds, we present a patient who underwent radical prostatectomy with bilateral pelvic lymphadenectomy, but had positive margins and subsequently developed local recurrence and then systemic disease. Pathologic and radiologic aspects of his disease are discussed. Therapeutic options at different stages of the disease are examined from the point of view of the urologist, radiation oncologist, and medical oncologist. The surgical portion of the discussion focuses on the selection of initial therapy. Both the selection of surgical candidates and choice of pre- or post-operative therapy in patients can be aided by prognostic tools looking at several variables, including prostate-specific antigen (PSA) level, Gleason score of the tumor, seminal vesicle invasion, extracapsular invasion, and lymph node involvement. Low-risk patients can be treated with monotherapy, such as radical prostatectomy, external beam radiation therapy, prostate brachytherapy, or cryosurgical ablation of the prostate. Higher risk patients may require adjuvant and possibly neoadjuvant therapy in addition. The radiation portion of the discussion focuses on the use of radiation therapy as salvage for relapsing disease. Of particular importance is the point that treating high-risk patients whose PSA levels have started to rise but are less than 1 ng/ml results in a long-term PSA control rate as high as 75%, but that limiting the use of salvage radiation therapy to patients with high PSA levels or biopsy confirmation of local recurrence in the face of a negative bone scan results in biochemical long-term control of less than 40%. In the medical oncology part of the discussion, the major focus is on the use of chemotherapy to treat patients whose disease has become resistant to hormonal therapy. Mitoxantrone plus a corticosteroid has been found to offer significant palliation for such patients. Combination therapy with estramustine plus taxanes, other microtubule inhibitors, or other agents such as topoisomerase II inhibitors, has been found to cause shrinkage of measurable soft tissue disease and diminution of serum PSA levels. The development of effective hormonal and chemotherapeutic drugs for treatment of metastatic disease has led to new interest in adjuvant and neoadjuvant therapy of high-risk patients.
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PMID:Progressing prostate carcinoma. 1130 30

Recently, accumulated statistical data indicate the protective effect of caffeine consumption against several types of cancer diseases. There are also reports about protective effect of caffeine and other xanthines against tumors induced by polycyclic aromatic hydrocarbons. One of the explanations is based on biological activation of such carcinogens by cytochromes that are also known for metabolism of caffeine. However, there is also numerous data indicating reverse effect on cytotoxicity of anticancer drugs that inhibit the action of topoisomerase I (e.g. Camptothecin or Topotecan) and topoisomerase II inhibitors (e.g. Doxorubicin, Mitoxantrone or mAMSA). In this work we tested the hypothesis that the caffeine protective effect is the result of sequestering of aromatic mutagens by formation of stacking (pi-pi) complexes. As the models for the study we have chosen two well-known mutagens, that do not require metabolical activation: quinacrine mustard(QM, aromatic, heterocyclic nitrogen mustard) and mechlorethamine (NM2, aliphatic nitrogen mustard). The flow cytometry study of these agents' action on the cell cycle of HL-60 cells indicated that caffeine prevents the cytotoxic action of QM, but not that of NM2. The formations of stacking complexes of QM with caffeine were confirmed by light absorption, calorimetric measurements and by molecular modeling calculation. Using the statistical thermodynamics calculations we calculated the "neighborhood" association constant (K(AC)=59+/-2M(-1)) and enthalpy change (DeltaH(0')=-116cal mol(-1)); the favorable entropy change of complex formation (DeltaS(0')=7.72cal mol(-1)K(-1), due to release of several water molecules, associated with components in the process of complex formation). The Gibbs' free energy change of QM-CAF formation is DeltaG(0')=-2.41kcal mol(-1). We were unable to detect any interaction between NM2 and caffeine either by spectroscopic or calorimetric measurement. In order to establish, whether the intercalation of QM plays any role in cytotoxic effect we tested, as a control, non-alkylatiatig, but also intercalating QM derivative-quinacrine (Q). The later had no cytostatic effect on HL-60 cell even at there order of higher concentration than QM or NM2 but, similar to QM forms (which we demonstrated) stacking complexes with caffeine (K(AC)=75+/-3M(-1)). These results strongly indicate, that the attenuating effect of caffeine on cytotoxic or mutagenic effects of some mutagens, is not the results of metabolic processes in the cells, but simply the physicochemical process of sequestering of aromatic molecules (potential carcinogens or mutagens) by formation of stacking complexes with them. The caffeine may then act as the "interceptor" of potential carcinogens (especially in the upper part of digesting track where its concentration can reach the concentration of mM level). There is, however, no indication either in the literature or in our experiments that xanthines can reverse the damage to nucleic acids when the damage to DNA has already occurred.
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PMID:The modulation of the DNA-damaging effect of polycyclic aromatic agents by xanthines. Part I. Reduction of cytostatic effects of quinacrine mustard by caffeine. 1199 30

Mantle cell lymphoma (MCL) is a mature B-cell proliferation characterized by the presence of translocation t(11;14)(q13;q32), an aggressive clinical course, and poor response to chemotherapy. The majority of drugs currently used in the treatment of lymphoproliferative disorders induce cell death by triggering apoptosis, but few data concerning drug-induced apoptosis in MCL have been reported. We have analysed the mechanisms of drug-induced cell death in four cell lines with the t(11;14) and in primary cells from 10 patients with MCL. Mitoxantrone, a topoisomerase II inhibitor, induced a strong cytotoxic effect in three cell lines (JVM-2, REC-1, and Granta 519), and in primary MCL cells. This cytotoxic effect due to apoptosis induction was observed despite the presence of either p53 or ATM abnormalities. However, no cytotoxic effect was detected after incubation with DNA-damaging agents in the NCEB-1 cell line, carrying p53 and ATM alterations, despite the presence of functional mitochondrial machinery. These results support that mitoxantrone can be effective in the treatment of MCL but that this activity requires the integrity of functional DNA-damage response genes.
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PMID:Activation of mitochondrial apoptotic pathway in mantle cell lymphoma: high sensitivity to mitoxantrone in cases with functional DNA-damage response genes. 1548 Apr 31

Mitoxantrone is a DNA topoisomerase II poison commonly used for the treatment of hormone-refractory prostate cancer. The risk of secondary leukaemia is well described after mitoxantrone treatment in breast cancer and multiple sclerosis. Recent improvements of systemic chemotherapy increased the median survival in patients becoming resistant to androgen deprivation from 10 to 18 months. As a consequence, chemotherapy-related cumulative toxicities may become a more prominent clinical problem in this patient population. We report here the first case report of secondary leukaemia induced by mitoxantrone in metastatic hormone-refractory prostate cancer. This clinical observation invites us to reconsider the number of administrations to be recommended for mitoxantrone-sensitive metastatic prostate cancer patients.
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PMID:Mitoxantrone-related acute myeloblastic leukaemia in a patient with metastatic hormone-refractory prostate cancer. 1715 10

Mitoxantrone is an anti-cancer agent used in the treatment of breast and prostate cancers. It is classified as a topoisomerase II poison, however can also be activated by formaldehyde to generate drug-DNA adducts. Despite identification of this novel form of mitoxantrone-DNA interaction, excessively high, biologically irrelevant drug concentrations are necessary to generate adducts. A search for mitoxantrone analogues that could potentially undergo this reaction with DNA more efficiently identified Pixantrone as an ideal candidate. An in vitro crosslinking assay demonstrated that Pixantrone is efficiently activated by formaldehyde to generate covalent drug-DNA adducts capable of stabilizing double-stranded DNA in denaturing conditions. Pixantrone-DNA adduct formation is both concentration and time dependent and the reaction exhibits an absolute requirement for formaldehyde. In a direct comparison with mitoxantrone-DNA adduct formation, Pixantrone exhibited a 10- to 100-fold greater propensity to generate adducts at equimolar formaldehyde and drug concentrations. Pixantrone-DNA adducts are thermally and temporally labile, yet they exhibit a greater thermal midpoint temperature and an extended half-life at 37 degrees C when compared to mitoxantrone-DNA adducts. Unlike mitoxantrone, this enhanced stability, coupled with a greater propensity to form covalent drug-DNA adducts, may endow formaldehyde-activated Pixantrone with the attributes required for Pixantrone-DNA adducts to be biologically active.
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PMID:Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent. 1748 12

Mitoxantrone is a DNA-topoisomerase 2 inhibitor used as a single agent for treatment of relapsing-remitting or progressive multiple sclerosis (MS). We present here two patients treated with mitoxantrone for MS who subsequently developed acute promyelocytic leukemia (APL). These constitute, to our knowledge, the eighth and ninth reports of APL in patients treated with mitoxantrone for MS. Topoisomerase 2 inhibitors are associated with therapy-related acute myeloid leukemia (t-AML) with 11q23 abnormalities, but therapy-related APL (t-APL) is less common, and documentation of nine cases of t-APL after mitoxantrone therapy for MS suggests a specific association.
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PMID:Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis. 1840 75

Mitoxantrone, the first immunosuppressant to receive FDA approval for treatment of worsening relapsing-remitting, secondary progressive, and progressive-relapsing multiple sclerosis (MS) is a DNA topoisomerase II inhibitor that has been associated with the development of acute promyelocytic myelogenous leukemia (APML). Central nervous system APML is a rare site of extramedullary involvement following mitoxantrone therapy. We report a patient with history of multiple sclerosis who developed bilateral optic nerve involvement as the primary manifestation of APML relapse following mitoxantrone treatment.
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PMID:Acute promyelocytic leukemic involvement of the optic nerves following mitoxantrone treatment for multiple sclerosis. 1868 47

NF-kappaB is activated by DNA-damaging anticancer drugs as part of the cellular stress response. However, the consequences of drug-induced NF-kappaB activation are still only partly understood. To investigate the impact of NF-kappaB on the cell's response to DNA damage, we engineered glioblastoma cells that stably express mutant IkappaBalpha superrepressor (IkappaBalpha-SR) to block NF-kappaB activation. Here, we identify a novel pro-apoptotic function of NF-kappaB in the DNA damage response in glioblastoma cells. Chemotherapeutic drugs that intercalate into DNA and inhibit topoisomerase II such as Doxorubicin, Daunorubicin and Mitoxantrone stimulate NF-kappaB DNA binding and transcriptional activity prior to induction of cell death. Importantly, specific inhibition of drug-induced NF-kappaB activation by IkappaBalpha-SR or RNA interference against p65 significantly reduces apoptosis upon treatment with Doxorubicin, Daunorubicin or Mitoxantrone. NF-kappaB exerts this pro-apoptotic function especially after pulse drug exposure as compared to continuous treatment indicating that the contribution of NF-kappaB becomes relevant during the recovery phase following the initial DNA damage. Mechanistic studies show that NF-kappaB inhibition does not alter Doxorubicin uptake and efflux or cell cycle alterations. Genetic silencing of p53 by RNA interference reveals that NF-kappaB promotes drug-induced apoptosis in a p53-independent manner. Intriguingly, drug-mediated NF-kappaB activation results in a significant increase in DNA damage prior to the induction of apoptosis. By demonstrating that NF-kappaB promotes DNA damage formation and apoptosis upon pulse treatment with DNA intercalators, our findings provide novel insights into the control of the DNA damage response by NF-kappaB in glioblastoma.
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PMID:Identification of a novel pro-apopotic function of NF-kappaB in the DNA damage response. 1972 19

DNA-damaging agents cause a multifaceted cellular stress response. Cells set in motion either repair mechanisms or programmed cell death pathways, depending on the extent of the damage and on their ability to withstand it. The RNA-binding protein (RBP) Sam68, which is up-regulated in prostate carcinoma, promotes prostate cancer cell survival to genotoxic stress. Herein, we have investigated the function of Sam68 in this cellular response. Mitoxantrone (MTX), a topoisomerase II inhibitor, induced relocalization of Sam68 from the nucleoplasm to nuclear granules, together with several other RBPs involved in alternative splicing, such as TIA-1, hnRNP A1 and the SR proteins SC35 and ASF/SF2. Sam68 accumulation in nuclear stress granules was independent of signal transduction pathways activated by DNA damage. Using BrU labelling and immunofluorescence, we demonstrate that MTX-induced nuclear stress granules are transcriptionally active foci where Sam68 and the phosphorylated form of RNA polymerase II accumulate. Finally, we show that MTX-induced relocalization of Sam68 correlates with changes in alternative splicing of its mRNA target CD44, and that MTX-induced CD44 splicing depends on Sam68 expression. These results strongly suggest that Sam68 is part of a RNA-mediated stress response of the cell that modulates alternative splicing in response to DNA damage.
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PMID:Genotoxic stress causes the accumulation of the splicing regulator Sam68 in nuclear foci of transcriptionally active chromatin. 2011 Feb 58


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