Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Gieseler, Frank; Bauer, Eckhard; Nuessler, V.; Clark, Michael J.; Valsamas, S.

doi:10.1038/sj.leu.2401570

Cited by 31 publications

(21 citation statements)

References 21 publications

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“…Several clear specific examples exist of in vitro induction of comet effects in mammalian cells by conditions which do not appear to be relevant to genotoxic potential at lower doses or which occur by mechanisms that do not involve direct interaction with DNA. These include the induction of comet effects by apoptosis inducers which inhibit topoisomerases (Boos & Stopper, 2000;Gieseler et al, 1999); cytokine treatment of cultured cells (Delaney et al, 1997); sodium dodecyl sulfate and potassium cyanide (Henderson et al, 1998); colchicine, dl-menthol and sodium acetate (Kiffe et al, 2003); luteolin (Michels et al, 2005); gossypol (Quintana et al, 2000), carbon tetrachloride (Sasaki et al, 1998) and vitamin C (Anderson et al, 1994). Further examples of induction of comet effects of questionable genotoxic biological significance include dietary flavonoids quercetin, myricetin and silymarin (Duthie et al, 1997); hemoglobin (Glei et al, 2006); olive oil extracts (Nousis et al, 2005) and capsaicin (Richeux et al, 1999).…”

Section: Significance Of Dna Damage Endpoint Resultsmentioning

confidence: 99%

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Kier

Kirkland²

2013

Critical Reviews in Toxicology

120

102

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An earlier review of the toxicity of glyphosate and the original Roundupä-branded formulation concluded that neither glyphosate nor the formulation poses a risk for the production of heritable/somatic mutations in humans. The present review of subsequent genotoxicity publications and regulatory studies of glyphosate and glyphosate-based formulations (GBFs) incorporates all of the findings into a weight of evidence for genotoxicity. An overwhelming preponderance of negative results in well-conducted bacterial reversion and in vivo mammalian micronucleus and chromosomal aberration assays indicates that glyphosate and typical GBFs are not genotoxic in these core assays. Negative results for in vitro gene mutation and a majority of negative results for chromosomal effect assays in mammalian cells add to the weight of evidence that glyphosate is not typically genotoxic for these endpoints in mammalian systems. Mixed results were observed for micronucleus assays of GBFs in nonmammalian systems. Reports of positive results for DNA damage endpoints indicate that glyphosate and GBFs tend to elicit DNA damage effects at high or toxic dose levels, but the data suggest that this is due to cytotoxicity rather than DNA interaction with GBF activity perhaps associated with the surfactants present in many GBFs. Glyphosate and typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures.

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Section: Significance Of Dna Damage Endpoint Resultsmentioning

confidence: 99%

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Kier

Kirkland²

2013

Critical Reviews in Toxicology

120

102

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“…We have demonstrated strongly decreased sensitivity to etoposide induced by both ATRA and PMA. It might be due to inhibition of topoisomerase II activity by etoposide -an effect which is the strongest in S phase [36]. Another possibility is increased efficiency of DNA repair processes mediated by p21 protein in cells stimulated to differentiation.…”

Section: Discussionmentioning

confidence: 99%

Effect of differentiating agents (all-trans retinoic acid and phorbol 12-myristate 13-acetate) on drug sensitivity of HL60 and NB4 cells in vitro.

Jasek

Mirecka²,

Litwin³

2008

Folia Histochem Cytobiol.

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Abstract:In vitro studies have shown that human myeloid leukemia cell lines: HL60 and NB4 can be stimulated to differentiation by various agents, for example, all-trans retinoic acid (ATRA) and phorbol 12-myristate 13-acetate (PMA). The purpose of this study was to investigate whether differentiation of HL60 and NB4 leukemia cell lines induced by ATRA and PMA alters their drug sensitivity. The differentiation along the neutrophil lineage (upon stimulation with ATRA) and along the monocyte/macrophage lineage (upon stimulation with PMA) was proved by decreased proliferative potential of cells, changes in their morphology, increased ability for NBT reduction and increased expression of CD11b and CD14 cell surface markers. The effect of drugs: cytosine arabinoside, daunorubicin, mitoxantrone and etoposide was examined by Alamar Blue test (proliferation and survival rates), as well as by evaluation of cell smears stained with Hoechst 33342 (apoptotic index). Differentiation resulted in the change of drug sensitivity in both cell lines: the differentiation along the neutrophil pathway (after stimulation with ATRA) increased sensitivity to cytosine arabinoside and mitoxantrone but decreased sensitivity to etoposide; the differentiation along the monocyte/macrophage pathway (induced by PMA) resulted in the decreased sensitivity of both cell lines to all drugs tested. In conclusion, we have shown that ATRA-and PMA-mediated differentiation of HL60 and NB4 cell lines results in the changes of their drug sensitivity. Our data may provide a contribution to a strategy aimed at a rational combination of differentiating agents and conventional anticancer drugs.

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“…Treatment with etoposide induces undirected DNA damage in vitro. 41 However, since topoisomerase uses telomeric DNA as a (a) hTERT mRNA expression determined by real-time RT-PCR. The values of untreated controls were averaged and defined as 100% (control).…”

Section: Discussionmentioning

confidence: 99%

DNA damage transiently increases TRF2 mRNA expression and telomerase activity

et al. 2003

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Telomerase activity transiently increases when HL60 cells are treated with the topoisomerase II inhibitor etoposide. A quantitative assessment revealed that telomerase is activated by etoposide treatment in a number of cell lines and that the increase is reversible after withdrawal of etoposide from the cell culture. Telomerase activation correlated with the occurrence of DNA damage but not with cell cycle arrest. We did not detect any transcriptional upregulation of hTERT mRNA, suggesting a post-transcriptional mechanism of telomerase activation. Furthermore, the mRNA expression of the telomere binding protein TRF2 was upregulated early and reversibly after etoposide treatment. TRF1 mRNA expression levels were unchanged after DNA damage, but increased when the cells accumulated in the G2/M phase. The data show that the telosome reacts after DNA damage by upregulating telomerase activity and TRF2 expression in malignant cells. It has previously been shown that overexpression of TRF2 can repress senescence signals arising from critically shortened telomeres. We show here that TRF2 is upregulated by undirected DNA damage that also affects the telomeric DNA. These data suggest that upregulation of telomerase activity and TRF2 expression might act as antiapoptotic mechanisms in the DNA-damage response of malignant cells. Leukemia (2003Leukemia ( ) 17, 2007Leukemia ( -2015 IntroductionThe chromosomal ends are composed of short repetitive DNA sequences and specialized telomere binding proteins. 1 The function of this 'telosome' is to protect the natural ends of the chromosomes from being recognized as artificial DNA breaks and to mediate chromosomal pairing and movement during cell division. 2 Immortal cells, such as germ line cells, stem cells and cancer cells, express the ribonucleoprotein telomerase, a reverse transcriptase, that synthesizes new telomeric repeats onto the chromosome ends and compensates for the loss occurring during cell division. 3 In most conditions analyzed so far, the limiting component of an active telomerase enzyme is the catalytic subunit hTERT. Upregulation of telomerase activity by enhanced proliferation of tumor cell lines or of sporadic tumors with high proliferation in vivo is virtually always mediated by a transcriptional overexpression of hTERT mRNA. 4 Although the predominant function of telomerase is maintenance of telomere length, some data indicate that the catalytic subunit hTERT additionally mediates a survival promoting function that is independent of its catalytic activity. 5,6 Inhibition of telomerase by targeting the catalytic subunit hTERT induces slow, proliferation-associated telomere shortening and finally senescence. 7,8 However, even before a critical telomere length is reached, the telomerase-inhibited cell lines show an increased sensitivity to DNA-damaging agents like etoposide. 8,9 Therefore, targeting telomerase simultaneously with DNA-damage-inducing agents might potentiate the effect of both therapeutic approaches.The telomere binding proteins TRF1 and TRF2 are...

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Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Cited by 31 publications

References 21 publications

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Effect of differentiating agents (all-trans retinoic acid and phorbol 12-myristate 13-acetate) on drug sensitivity of HL60 and NB4 cells in vitro.

DNA damage transiently increases TRF2 mRNA expression and telomerase activity

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