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Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA

Amsacrine is an anilinoacridine derivative anticancer drug, used to treat a wide variety of malignancies. In cells, amsacrine poisons topoisomerase 2 by stabilizing DNA-drug-enzyme ternary complex. Presence of amsacrine increases the steady-state concentration of these ternary complexes which in tur...

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Autores principales: Jangir, Deepak K., Kundu, Suman, Mehrotra, Ranjana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726726/
https://www.ncbi.nlm.nih.gov/pubmed/23922861
http://dx.doi.org/10.1371/journal.pone.0069933
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author Jangir, Deepak K.
Kundu, Suman
Mehrotra, Ranjana
author_facet Jangir, Deepak K.
Kundu, Suman
Mehrotra, Ranjana
author_sort Jangir, Deepak K.
collection PubMed
description Amsacrine is an anilinoacridine derivative anticancer drug, used to treat a wide variety of malignancies. In cells, amsacrine poisons topoisomerase 2 by stabilizing DNA-drug-enzyme ternary complex. Presence of amsacrine increases the steady-state concentration of these ternary complexes which in turn hampers DNA replication and results in subsequent cell death. Due to reversible binding and rapid slip-out of amsacrine from DNA duplex, structural data is not available on amsacrine-DNA complexes. In the present work, we designed five oligonucleotide duplexes, differing in their minor groove widths and hydration pattern, and examined their binding with amsacrine using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Complexes of amsacrine with calf thymus DNA were also evaluated for a comparison. Our results demonstrate for the first time that amsacrine is not a simple intercalator; rather mixed type of DNA binding (intercalation and minor groove) takes place between amsacrine and DNA. Further, this binding is highly sensitive towards the geometries and hydration patterns of different minor grooves present in the DNA. This study shows that ligand binding to DNA could be very sensitive to DNA base composition and DNA groove structures. Results demonstrated here could have implication for understanding cytotoxic mechanism of aminoacridine based anticancer drugs and provide directions to modify these drugs for better efficacy and few side-effects.
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spelling pubmed-37267262013-08-06 Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA Jangir, Deepak K. Kundu, Suman Mehrotra, Ranjana PLoS One Research Article Amsacrine is an anilinoacridine derivative anticancer drug, used to treat a wide variety of malignancies. In cells, amsacrine poisons topoisomerase 2 by stabilizing DNA-drug-enzyme ternary complex. Presence of amsacrine increases the steady-state concentration of these ternary complexes which in turn hampers DNA replication and results in subsequent cell death. Due to reversible binding and rapid slip-out of amsacrine from DNA duplex, structural data is not available on amsacrine-DNA complexes. In the present work, we designed five oligonucleotide duplexes, differing in their minor groove widths and hydration pattern, and examined their binding with amsacrine using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Complexes of amsacrine with calf thymus DNA were also evaluated for a comparison. Our results demonstrate for the first time that amsacrine is not a simple intercalator; rather mixed type of DNA binding (intercalation and minor groove) takes place between amsacrine and DNA. Further, this binding is highly sensitive towards the geometries and hydration patterns of different minor grooves present in the DNA. This study shows that ligand binding to DNA could be very sensitive to DNA base composition and DNA groove structures. Results demonstrated here could have implication for understanding cytotoxic mechanism of aminoacridine based anticancer drugs and provide directions to modify these drugs for better efficacy and few side-effects. Public Library of Science 2013-07-29 /pmc/articles/PMC3726726/ /pubmed/23922861 http://dx.doi.org/10.1371/journal.pone.0069933 Text en © 2013 Jangir et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jangir, Deepak K.
Kundu, Suman
Mehrotra, Ranjana
Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA
title Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA
title_full Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA
title_fullStr Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA
title_full_unstemmed Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA
title_short Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA
title_sort role of minor groove width and hydration pattern on amsacrine interaction with dna
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726726/
https://www.ncbi.nlm.nih.gov/pubmed/23922861
http://dx.doi.org/10.1371/journal.pone.0069933
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