ArticleBioorganic & medicinal chemistry letters2012
Chromatin structure determines accessibility of a hairpin polyamide-chlorambucil conjugate at histone H4 genes in pancreatic cancer cells.
Article in Bioorganic & medicinal chemistry letters, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 21 citations in OpenAlex.
- Influence of Kv11.1 (hERG1) KPflugers Archiv : European journal of physiology · 2021Article
- Article
- Prognostic prediction of a 12-methylation gene-based risk score system on pancreatic adenocarcinoma.Oncology letters · 2020Article
- The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding.Biomolecules · 2020Review
- Synthetic genome readers target clustered binding sites across diverse chromatin states.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Deciphering the genomic targets of alkylating polyamide conjugates using high-throughput sequencing.Nucleic acids research · 2016Article
- Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC (Crosslinking of Small Molecules to Isolate Chromatin).Journal of visualized experiments : JoVE · 2016Article
- Identification of Binding Targets of a Pyrrole-Imidazole Polyamide KR12 in the LS180 Colorectal Cancer Genome.PloS one · 2016Article
- Mapping polyamide-DNA interactions in human cells reveals a new design strategy for effective targeting of genomic sites.Angewandte Chemie (International ed. in English) · 2014Article
- Profiling of the Chromatin-associated Proteome Identifies HP1BP3 as a Novel Regulator of Cell Cycle Progression.Molecular & cellular proteomics : MCP · 2014Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
We have shown that a specific pyrrole-imidazole polyamide-DNA alkylator (chlorambucil) conjugate, 1R-Chl, alters the growth characteristics of various cancer cell lines in culture, and causes these cells to arrest in the G2/M stage of the cell cycle, without apparent cytotoxicity. This molecule has also shown efficacy in several mouse xenograft models, preventing tumor growth. Previous microarray studies have suggested that members of the histone H4 gene family, H4c and H4j/k, are the primary targets of this molecule, leading to reduced histone mRNA synthesis and growth arrest in cancer cells. In the present study, we examine the effects of 1R-Chl on transcription of other members of the H4 gene family, with the result that mRNA transcription of most genomic copies of H4 are down-regulated by 1R-Chl in a human pancreatic cancer cell line (MIA PaCa-2), but not in a cell line of non-cancerous origin (HEK293 cells). The basis for this differential effect is likely an open chromatin conformation within the H4 genes in cancer cells. Chromatin immunoprecipitation experiments show increased histone acetylation on the histone H4 genes in cancer cells, compared to HEK293 cells, explaining the differential activity of this molecule in cancer versus non-cancer cells.
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