Topoisomerase Poisons: Harnessing the Dark Side of Enzyme Mechanism

Froelich-Ammon, Stacie J.; Osheroff, Neil

doi:10.1074/jbc.270.37.21429

Cited by 501 publications

(412 citation statements)

References 67 publications

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“…It traps the topoisomerase I enzyme once it has performed a nick in a DNA strand, and prevents the religation of the nick (Froelich-Ammon and Oshero , 1995). Subsequent interaction of the DNA-topoisomerase I-CPT complex with a replication fork or a transcription machinery causes the breakage of DNA (double-strand breaks) (Froelich-Ammon and Oshero , 1995;Nitiss and Wang, 1996) and leads to cell death.…”

Section: Introductionmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kB. It is activated by various stress situations, including oxidative stress, and by DNAdamaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NFkB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.

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Section: Introductionmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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“…Topo II has been identified as the primary cellular target for many of the most effective and widely used anti-cancer drugs, including etoposide, mitoxantrone, epirubicin and doxorubicin (reviewed in Pommier, 1993;Froelich-Ammon and Osheroff, 1995). However, the development of drug resistance limits the clinical efficacy of these topo II-targeting agents.…”

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confidence: 99%

Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors

Davies

Bergh²,

Harris³

et al. 1997

Br J Cancer

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Summary We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase 11 (topo 11) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo 11. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo lla and/or -1, did not confer ICRF-159 resistance. Indeed, marked topo Ila down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo 11 inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo lla, not topo llp, is more likely to be the major in vivo target for ICRF-159.

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“…In particular, the 170 kDa topoisomerase II alpha isoform is closely associated with the cell cycle, being highly expressed during cellular proliferation, and is the primary target of such topoisomerase II inhibitors as doxorubicin or etoposide (Burden and Osheroff, 1998). These drugs selectively exploit the catalytic activity of topoisomerase II alpha to create DNA damage by increasing the frequency and duration of DNA cleavage sites, causing permanent doublestranded breaks and leading to apoptosis (Froelich-Ammon and Osheroff, 1995;Beck et al, 1999;Mow et al, 2001). Owing to this mechanism of toxicity, increased enzyme level is associated with enhanced sensitivity, and drug resistance is related with reduced topoisomerase II alpha level (Beck et al, 1993, Oloumi et al, 2000.…”

Section: Discussionmentioning

confidence: 99%

“…Topoisomerase II inhibitors are widely used agents in cancer treatment (Froelich-Ammon and Osheroff, 1995), exploiting the catalytic activity of topoisomerase II alpha by increasing permanent DNA damage (Beck et al, 1999). Previous findings have shown that DNA damage mediated by topoisomerase II inhibitors induces apoptosis (Beck et al, 1999;Mow et al, 2001), particularly through cytochrome c release (Liu et al, 1996;Kluck et al, 1997), Apaf-1 involvement (Perkins et al, 2000;Lauber et al, 2001), and subsequent caspase-9 activation (Mow et al, 2001).…”

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confidence: 99%

CD26/dipeptidyl peptidase IV enhances expression of topoisomerase II alpha and sensitivity to apoptosis induced by topoisomerase II inhibitors

et al. 2003

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CD26/dipeptidyl peptidase IV (DPPIV) is a cell surface-bound ectopeptidase with important roles in T-cell activation and tumour biology. We now report that CD26/DPPIV enhances sensitivity to apoptosis induced by the antineoplastic agents doxorubicin and etoposide. In particular, CD26/DPPIV presence is associated with increased susceptibility to the mitochondrial pathway of apoptosis, documented by enhanced cleavage of poly (ADP ribose) polymerase (PARP), caspase-3 and caspase-9, Bcl-xl, and Apaf-1, as well as increased expression of death receptor 5 (DR5). We also show that the caspase-9-specific inhibitor z-LEHD-fmk inhibits drugmediated apoptosis, leading to decreased PARP and caspase-3 cleavage, and reduced DR5 expression. Importantly, through detailed studies that demonstrate the association between topoisomerase II alpha expression and DPPIV activity, our data provide further evidence of the key role played by CD26 in biological processes.

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Topoisomerase Poisons: Harnessing the Dark Side of Enzyme Mechanism

Cited by 501 publications

References 67 publications

The ATM protein is required for sustained activation of NF-κB following DNA damage

The ATM protein is required for sustained activation of NF-κB following DNA damage

Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors

CD26/dipeptidyl peptidase IV enhances expression of topoisomerase II alpha and sensitivity to apoptosis induced by topoisomerase II inhibitors

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