Analysis of streptonigrin‐induced incomplete chromosome elements and interstitial fragments in Chinese hamster cells using a telomeric PNA probe

Bolzán, Alejandro D.; Bianchi, Martha S.

doi:10.1002/em.20051

Cited by 13 publications

(19 citation statements)

References 24 publications

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“…1A). On the other hand, the high spontaneous frequency of IC and acentric fragments observed in control cells (Table 1a) cannot be linked to the results of the FISH analysis and is similar to that found in other mammalian cell lines, previously investigated in our laboratory for telomere instability [17,[30][31][32]. Furthermore, the significant increase in the frequency of telomere FISH signal loss found in control cells 10 and 15 days after treatment (Table 1b) could be due to spontaneous extensive telomere shortening, a phenomenon usually observed in in vitro cultured cells [1][2][3][4].…”

Section: Chromosome Damage and Distribution Pattern Of Telomeric Sequsupporting

confidence: 75%

The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells

Paviolo

Santiñaque

Castrogiovanni

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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We analyzed chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the methylating agent and antineoplastic/diabetogenic drug streptozotocin (STZ), to test whether it induces long-term telomere instability (by chromosome end loss and/or telomere dysfunction). Rat cells (ADIPO-P2 cell line, derived from Sprague-Dawley rat adipose cells) were treated with a single concentration of STZ (2mM). Chromosomal aberrations were analyzed 18h, 10 days, and 15 days after treatment, using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of chromosomal aberrations in STZ-exposed cultures vs. untreated cultures at each time point analyzed. The yield of induced aberrations was very similar at each time point. Induction of aberrations not involving telomere dysfunction was only observed 18h and 15 days after treatment, whereas induction of telomere dysfunction-related aberrations by STZ (mainly in the form of telomere FISH signal loss and duplications, most of them chromatid-type aberrations) was observed at each time point. Our results show that STZ induces persistent telomere instability in mammalian cells, cytogenetically manifested as telomere dysfunction-related chromosomal aberrations. Neither telomere length nor telomerase activity is related to the telomere dysfunction.

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Section: Chromosome Damage and Distribution Pattern Of Telomeric Sequsupporting

confidence: 75%

The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells

Paviolo

Santiñaque

Castrogiovanni

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…30 The mechanism(s) behind the cytotoxic nature of streptonigrin likely include DNA strand scission, Topoisomerase II-mediated DNA cleavage, the formation of DNA-damaging reactive oxygen species (ROS), and possibly PAD inhibition. 23,24,27,31,32 To determine if our keyanalogues possess selective anti-proliferative activities that might show greater efficacy in PAD-associated cancers, we assessed their biological activities by measuring cell viability in U2OS cells, an osteosarcoma cell line that overexpresses PAD4 and NIH 3T3 cells, a mouse embryonic fibroblast cell line. 11 At 10 μM, compound 3 , 14 and 21 are most effective in killing both U2OS and NIH 3T3 cells with ≤30% of cells remaining viable.…”

Section: Resultsmentioning

confidence: 99%

Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation

Dreyton

Anderson

Subramanian

et al. 2014

Bioorganic & Medicinal Chemistry

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Protein citrullination is just one of more than 200 known PTMs. This modification, catalyzed by the Protein Arginine Deiminases (PADs 1–4 and PAD6 in humans), converts the positively charged guanidinium group of an arginine residue into a neutral ureido-group. Given the strong links between dysregulated PAD activity and human disease, we initiated a program to develop PAD inhibitors as potential therapeutics for these and other diseases in which the PADs are thought to play a role. Streptonigrin which possesses both anti-tumor and anti-bacterial activity was later identified as a highly potent PAD4 inhibitor. In an effort to understand why streptonigrin is such a potent and selective PAD4 inhibitor, we explored its structure-activity relationships by examining the inhibitory effects of several analogues that mimic the A, B, C, and/or D rings of streptonigrin. We report the identification of the 7-amino-quinoline-5,8-dione core of streptonigrin as a highly potent pharmacophore that acts as a pan-PAD inhibitor.

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“…Possible mechanisms to explain the predominance of some types of ICE over the others are discussed elsewhere Bolzán and Bianchi, 2004b.…”

Section: Discussionmentioning

confidence: 99%

A comparative analysis of bleomycin‐induced incomplete chromosome elements in two mammalian cell lines using a telomeric PNA probe

Flaqué

Bianchi

Bolzán

2006

Environ and Mol Mutagen

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Fluorescence in situ hybridization (FISH) with a telomeric peptide nucleic acid probe was employed to analyze the induction of incomplete chromosome elements (ICE; i.e., incomplete chromosomes and terminal fragments) by bleomycin (BLM) in two mammalian cell lines. Chinese hamster embryo cells (CHE cell line, average 2n = 23) and domestic rabbit cells (CPC cell line, average 2n = 44) were treated with 2.5 micro g/ml BLM; after 18 hr of incubation, first-division metaphases were stained with the telomeric probe, and ICE and other unstable chromosomal aberrations were scored. BLM induced ICE, dicentrics, and interstitial acentric fragments in CHE cells, but only ICE in CPC cells. About 50% of the metaphases in BLM-treated CHE cells contained one or more pairs of ICE, while only 20% of treated CPC cells contained ICE. Almost 100% of the BLM-induced ICE in both cell lines consisted of pairs formed by an incomplete chromosome and a terminal fragment. Our results confirm that ICE are the most frequent type of unstable chromosomal aberration induced by BLM in mammalian cells. Moreover, the present study shows that an increase in the chromosome number does not necessarily result in an increase in the frequency of BLM-induced ICE. The results also show that the difference in the chromosomal sensitivity to BLM in CHE and CPC cells is due to differences in the absolute frequency but not in the pattern (i.e., type and proportion) of ICE.

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Analysis of streptonigrin‐induced incomplete chromosome elements and interstitial fragments in Chinese hamster cells using a telomeric PNA probe

Cited by 13 publications

References 24 publications

The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells

The methylating agent streptozotocin induces persistent telomere dysfunction in mammalian cells

Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation

A comparative analysis of bleomycin‐induced incomplete chromosome elements in two mammalian cell lines using a telomeric PNA probe

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