A Two-drug Model for Etoposide Action against Human Topoisomerase IIα

Bromberg, Kenneth D.; Burgin, Alex B.; Osheroff, Neil

doi:10.1074/jbc.m212056200

Cited by 129 publications

(151 citation statements)

References 56 publications

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“…Etoposide occupancy at both scissile bonds is required for DSBs, and most breaks formed at concentrations relevant to chemotherapy are SSNs (Bromberg et al 2003). Consistent with reports in which the vast majority of detected TOP2 cleavage events were SSNs (Bromberg et al 2003;Muslimovic et al 2009), we found 1.3%-3.4% of TOP2A cleavage events were DSBs and the remainder were SSNs (Supplemental Table S1; Supplemental Fig.…”

Section: Top2a Cleavage Events Are Ssns More Often Than Dsbssupporting

confidence: 77%

Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

Davenport

Urtishak

et al. 2017

Genome Res.

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Type II topoisomerases orchestrate proper DNA topology, and they are the targets of anti-cancer drugs that cause treatment-related leukemias with balanced translocations. Here, we develop a high-throughput sequencing technology to define TOP2 cleavage sites at single-base precision, and use the technology to characterize TOP2A cleavage genome-wide in the human K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence preferences, occurs in cleavage cluster regions (CCRs), and is enriched in introns and lincRNA loci. TOP2A CCRs are biased toward the distal regions of gene bodies, and TOP2 poisons cause a proximal shift in their distribution. We find high TOP2A cleavage levels in genes involved in translocations in TOP2 poison-related leukemia. In addition, we find that a large proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. Comparisons to ENCODE data reveal distinct TOP2A CCR clusters that overlap with marks of transcription, open chromatin, and enhancers. Our findings implicate TOP2A cleavage as a broad DNA damage mechanism in oncogenic translocations as well as a functional role of TOP2A cleavage in regulating transcription elongation and gene activation.

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Section: Top2a Cleavage Events Are Ssns More Often Than Dsbssupporting

confidence: 77%

Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

Davenport

Urtishak

et al. 2017

Genome Res.

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“…A possible explanation for this additive effect is the different mechanisms of action against topo II conferred by the two drugs. Bromberg et al (2003b) have shown that VP-16 acts by inhibiting the ability of topo II to ligate cleaved DNA molecules, whereas quinolones have little effect on ligation but stimulate the forward rate of topo II-mediated DNA cleavage. These two distinct mechanisms may work in concert and lead to the observed additivity in the antiproliferative effects of VP-16 and MXF.…”

Section: Discussionmentioning

confidence: 99%

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

et al. 2006

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Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8-and 2.6-fold decrease in cell proliferation, respectively) (Po0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8-and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (Po0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 mg ml À1 VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 mg ml À1 VP-16 (Po0.001). VP-16 enhanced the release of IL-1b and TNF-a from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (Po0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.

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“…rical Top2cc in which only one DNA strand is cleaved at any given time (8,32,33). Therefore, the tyrosine from a trapped topoisomerase can be linked to different types of DNA ends.…”

Section: Ribonucleotide Incorporation Enhances Irreversible Top2cc Bumentioning

confidence: 99%

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

Gao

Schellenberg

Huang

et al. 2014

Journal of Biological Chemistry

109

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Background: TDP2 is critical for repairing Top2 cleavage complexes (Top2cc) and as the VPg unlinkase for picornavirus replication. Results: Top2 proteolysis or denaturation is required for TDP2 activity. TDP2 also hydrolyzes Top2cc at ribonucleotides. Conclusion: TDP2 efficiently disjoints relatively large Top2 polypeptide-DNA and -RNA complexes. Significance: Top2 processing is critical prior to its unlinking from DNA or RNA by TDP2.

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A Two-drug Model for Etoposide Action against Human Topoisomerase IIα

Cited by 129 publications

References 56 publications

Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

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