Culprit and victim – DNA topoisomerase II

Kellner, Udo; Sehested, Maxwell; Jensen, Peter Buhl; Gieseler, Frank; Rudolph, Pierre

doi:10.1016/s1470-2045(02)00715-5

Cited by 146 publications

(141 citation statements)

References 60 publications

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“…(67) Such binding interferes with the re-ligation step of the topoisomerase resulting in double-stranded DNA breaks. (66) Concluding remarks As has been described in the previous sections, DNA intercalation of anthracyclines leads to changes in chromatin supercoiling that eventually result in chromatin aggregation. (23) DNA intercalation still remains one of the main targeting sites for the binding of these drugs to DNA.…”

Section: Introductionmentioning

confidence: 71%

“…(63) The intercalation process itself results in a distortion of the DNA conformation that causes the inhibition of Topo II. (64) The effects of anthracyclines on this enzyme (65) have been extensively studied (see (66) for a review). In this instance, the mechanism of action involves the binding of the drug to the Topo IIa-DNA complexes forming a ternary complex.…”

Section: Introductionmentioning

confidence: 99%

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The anthracycline antibiotics: antitumor drugs that alter chromatin structure

2004

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SummaryAnthracycline antibiotics are an important group of antitumor drugs widely used in cancer chemotherapy. However, despite the increasing interest in these chemotherapeutic agents, their mechanism of action is not yet completely understood. Here, we review what is currently known about the molecular mechanisms involved with special emphasis on the interaction of these drugs with chromatin and its constitutive components: DNA and histones. The evidence suggests that one very important component of the activity of these drugs is the result of these manifold interactions that lead to a chromatin unfolding and aggregation. This chromatin structural disruption is likely to interfere with the metabolic processes of DNA (replication and transcription) and it may play an important role in the apoptosis undergone by the cells upon treatment with these drugs.

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Section: Introductionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

The anthracycline antibiotics: antitumor drugs that alter chromatin structure

2004

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“…The molecular target of drug action for amino acridines, anthracyclines and epipodophyllotoxins has been reported to be topoisomerase (Zwelling et al, 1989). Multiple resistance to Topo II poisons exist in two major forms: one is attributable to an efflux pump in the cell membrane that lowers the steady-state concentration of the drug at the target site, and in the other form, the activity and sensitivity of the target enzyme Topo II itself are decreased by downregulation or mutation (Kellner et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…From a clinical perspective, mutations in Topo II do not seem to have a major role in resistance (Kudo et al, 1996;Kellner et al, 2002). In addition to these findings, forced induction of Topo IIa gene expression in etoposide-resistant cell lines using a dexamethasone inducible vector or a recombinant adenovirus vector containing normal human or drosophila Topo IIa overcame etoposide resistance (Asano et al, 1996a -c;Zhang et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Altered expression of topoisomerase IIα contributes to cross-resistant to etoposide K562/MX2 cell line by aberrant methylation

et al. 2005

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KRN 8602 (MX2) is a novel morpholino anthracycline derivative having the chemical structure 3 0 -deamino-3 0 -morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. To investigate the mechanisms of resistance to MX2, we established an MX2-resistant phenotype (K562/MX2) of the human myelogeneous leukaemia cell line (K562/P), by continuously exposing a suspension culture to increasing concentrations of MX2. K562/MX2 cells were more resistant to MX2 than the parent cells, and also showed crossresistance to etoposide and doxorubicin. Topoisomerase (Topo) IIa protein levels in K562/MX2 cells were lower of those in K562/P cells on immunoblot analysis and decreased expression of Topo IIa mRNA was seen in K562/MX2 cells. Topoisomerase II catalytic activity was also reduced in the nuclear extracts from K562/MX2 cells when compared with K562/P cells. Aberrant methylated CpG of Topo IIa gene was observed in K562/MX2 cells when compared with the parent line on methylation-specific restriction enzyme analysis. To overcome the drug resistance to MX2 and etoposide, we investigated treatment with 5-Aza-2 0 -deoxycytidine (5AZ), which is a demethylating agent, in K562/MX2 cells. 5-Aza-2 0 -deoxycytidine treatment increased Topo IIa mRNA expression in K562/ MX2 cells, but not in K562/P cells, and increased the cytotoxicity of MX2 and etoposide. Methylated CpG was decreased in K562/ MX2 cells after 5AZ treatment. We concluded that the mechanism of drug resistance to MX2 and etoposide in K562/MX2 cells might be the combination of decreased expression of Topo IIa gene and increased methylation, and that 5AZ could prove to be a novel treatment for etoposide-resistant cell lines, such as K562/MX2.

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“…Topo II is an ATP-dependent enzyme that catalyzes changes in DNA topology necessary for transcription, replication, and chromosome condensation and segregation (2,3). Because topo II is essential for DNA replication, it has been identified as an important drug target in the treatment of cancer.…”

Section: Introductionmentioning

confidence: 99%

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

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Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracenecontaining topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-hour treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.

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Culprit and victim – DNA topoisomerase II

Cited by 146 publications

References 60 publications

The anthracycline antibiotics: antitumor drugs that alter chromatin structure

The anthracycline antibiotics: antitumor drugs that alter chromatin structure

Altered expression of topoisomerase IIα contributes to cross-resistant to etoposide K562/MX2 cell line by aberrant methylation

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

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