Murine Transgenic Cells Lacking DNA Topoisomerase IIβ Are Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and Cleavable Complex Formation

Errington, Fiona; Willmore, Elaine; Tilby, Michael J.; Li, L.; Li, G.; Li, W.; Baguley, Bruce C.; Austin, Caroline A.

doi:10.1124/mol.56.6.1309

Cited by 86 publications

(96 citation statements)

References 30 publications

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“…The most robust potentiation was observed with mitoxantrone and mAMSA, while marginal potentiation was obtained for etoposide and no significant effect was seen for doxorubicin or epirubicin. Cells lacking topoisomerase IIβ have previously been shown to be resistant to mitoxantrone and mAMSA, 28,29 indicating a significant role for this isozyme in the cytotoxicity of these drugs, whereas the degree of resistance to etoposide or doxorubicin in topoisomerase IIβ null cells was smaller. Similarly, we found the IC 50 for mitoxantrone in growth inhibition assays is five times higher in topoisomerase IIβ null Nalm-6 cells than in their wild type counterparts while the ratio is only 2.8 for etoposide (data not shown).…”

Section: Discussionmentioning

confidence: 89%

“…24 Recently, specific roles in transcription regulation and sperm chromatin remodelling have been uncovered for topoisomerase IIβ. [25][26][27] The topoisomerase IIα isoform is the major target for most clinically-relevant topoisomerase poisons including etoposide and epirubicin 12,28,29 although the -β isoform appears to contribute more for some topoisomerase poisons including mitoxantrone, mAMSA and XK469. [28][29][30] Several mechanisms could explain the sensitization of cells to topoisomerase poisons by HDAC inhibitors 13,15,31 but notably, it was recently reported that this potentiation is mediated specifically through topoisomerase IIβ.…”

Section: Histone Deacetylase Inhibition Redistributes Topoisomerase Imentioning

confidence: 99%

See 1 more Smart Citation

Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin

Cowell¹,

Papageorgiou²,

Padget³

et al. 2011

nucleus

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Section: Discussionmentioning

confidence: 89%

Section: Histone Deacetylase Inhibition Redistributes Topoisomerase Imentioning

confidence: 99%

Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin

Cowell¹,

Papageorgiou²,

Padget³

et al. 2011

nucleus

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“…The HL-60 cell line and its mitoxantrone-resistant (TOP2-deficient) variant, HL-60͞MX2, were obtained from the American Type Culture Collection (17). The simian virus 40-transformed TOP2␤ knockout mouse embryo fibroblast cell line TOP2␤(Ϫ͞Ϫ) and its parental simian virus 40-transformed TOP2␤(ϩ͞ϩ) cell line were cultured under the same condition (18).…”

Section: Methodsmentioning

confidence: 99%

The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway

Xiao

Mao

Desai

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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It has been proposed that the topoisomerase II (TOP2)␤-DNA covalent complex arrests transcription and triggers 26S proteasome-mediated degradation of TOP2␤. It is unclear whether the initial trigger for proteasomal degradation is due to DNA damage or transcriptional arrest. In the current study we show that the TOP2 catalytic inhibitor 4,4-(2,3-butanediyl)-bis(2,6-piperazinedione) (ICRF-193), which traps TOP2 into a circular clamp rather than the TOP2-DNA covalent complex, can also arrest transcription. Arrest of transcription, which is TOP2␤-dependent, is accompanied by proteasomal degradation of TOP2␤. Different from TOP2 poisons and other DNA-damaging agents, ICRF-193 did not induce proteasomal degradation of the large subunit of RNA polymerase II. These results suggest that proteasomal degradation of TOP2␤ induced by the TOP2-DNA covalent complex or the TOP2 circular clamp is due to transcriptional arrest but not DNA damage. By contrast, degradation of the large subunit of RNA polymerase II is due to a DNA-damage signal.

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“…Indeed, two studies suggested that Top2␣, rather than Top2␤, was the determinant of cytotoxic effects of etoposide (27,28). Even more intriguingly, Azarova et al (27) suggested that Top2␤ may be responsible for the development of secondary malignancy associated with etoposide treatment.…”

Section: Dna Topoisomerase II (Top2)mentioning

confidence: 99%

NK314, a Topoisomerase II Inhibitor That Specifically Targets the α Isoform

Toyoda

Kagaya

Cowell

et al. 2008

Journal of Biological Chemistry

108

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Topoisomerase II (Top2) is a ubiquitous nuclear enzyme that relieves torsional stress in chromosomal DNA during various cellular processes. Agents that target Top2, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective anticancer drugs used in the clinic. Mammalian cells possess two genetically distinct Top2 isoforms, both of which are the target of these agents. Top2␣ is essential for cell proliferation and is highly expressed in vigorously growing cells, whereas Top2␤ is nonessential for growth and has recently been implicated in treatment-associated secondary malignancies, highlighting the validity of a Top2␣-specific drug for future cancer treatment; however, no such agent has been hitherto reported. Here we show that NK314, a novel synthetic benzo[c]phenanthridine alkaloid, targets Top2␣ and not Top2␤ in vivo. Unlike other Top2 inhibitors, NK314 induces Top2-DNA complexes and double-strand breaks (DSBs) in an ␣ isoform-specific manner. Heterozygous disruption of the human TOP2␣ gene confers increased NK314 resistance, whereas TOP2␤ homozygous knock-out cells display increased NK314 sensitivity, indicating that the ␣ isoform is the cellular target. We further show that the absence of Top2␤ does not alleviate NK314 hypersensitivity of cells deficient in non-homologous end-joining, a critical pathway for repairing Top2-mediated DSBs. Our results indicate that NK314 acts as a Top2␣-specific poison in mammalian cells, with excellent potential as an efficacious and safe chemotherapeutic agent. We also suggest that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents. DNA topoisomerase II (Top2)2 is a ubiquitous nuclear enzyme that alters the topological structure of DNA and chromosomes through a transient DNA double-strand break (DSB) and subsequent religation of the DSB (1, 2). The enzyme has been implicated in many aspects of DNA metabolism, including DNA replication, repair, transcription, and chromosome condensation/segregation (1, 3). Top2 has been of considerable interest to human medicine, because it is an important target for cancer chemotherapy (4). Top2-targeting agents, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective and widely used anticancer drugs in cancer chemotherapy (5, 6). These agents are referred to as "Top2 poisons," because they convert the essential enzyme into a highly cytotoxic DNA-damaging agent through the formation of "cleavage complex" (also called "cleavable complex"), in which a Top2-linked DNA strand-passing intermediate is stabilized, allowing the generation of a DSB (7,8).Mammalian cells possess two genetically distinct Top2 isoforms (9, 10). Despite their similar structural features (ϳ70% identity at the amino acid level) and biological properties, the two isoforms are differentially regulated and play different roles in living cells. Top2␣ is most abundantly expressed in rapidly growing tissues and its expression is cell cycle-regulated...

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Murine Transgenic Cells Lacking DNA Topoisomerase IIβ Are Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and Cleavable Complex Formation

Cited by 86 publications

References 30 publications

Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin

Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin

The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway

NK314, a Topoisomerase II Inhibitor That Specifically Targets the α Isoform

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