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A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer
We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468576/ https://www.ncbi.nlm.nih.gov/pubmed/26077929 http://dx.doi.org/10.1038/srep11385 |
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author | Ohnmacht, Stephan A Marchetti, Chiara Gunaratnam, Mekala Besser, Rachael J Haider, Shozeb M Di Vita, Gloria Lowe, Helen L Mellinas-Gomez, Maria Diocou, Seckou Robson, Mathew Šponer, Jiri Islam, Barira Barbara Pedley, R Hartley, John A Neidle, Stephen |
author_facet | Ohnmacht, Stephan A Marchetti, Chiara Gunaratnam, Mekala Besser, Rachael J Haider, Shozeb M Di Vita, Gloria Lowe, Helen L Mellinas-Gomez, Maria Diocou, Seckou Robson, Mathew Šponer, Jiri Islam, Barira Barbara Pedley, R Hartley, John A Neidle, Stephen |
author_sort | Ohnmacht, Stephan A |
collection | PubMed |
description | We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41. |
format | Online Article Text |
id | pubmed-4468576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-44685762015-06-18 A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer Ohnmacht, Stephan A Marchetti, Chiara Gunaratnam, Mekala Besser, Rachael J Haider, Shozeb M Di Vita, Gloria Lowe, Helen L Mellinas-Gomez, Maria Diocou, Seckou Robson, Mathew Šponer, Jiri Islam, Barira Barbara Pedley, R Hartley, John A Neidle, Stephen Sci Rep Article We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41. Nature Publishing Group 2015-06-16 /pmc/articles/PMC4468576/ /pubmed/26077929 http://dx.doi.org/10.1038/srep11385 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Ohnmacht, Stephan A Marchetti, Chiara Gunaratnam, Mekala Besser, Rachael J Haider, Shozeb M Di Vita, Gloria Lowe, Helen L Mellinas-Gomez, Maria Diocou, Seckou Robson, Mathew Šponer, Jiri Islam, Barira Barbara Pedley, R Hartley, John A Neidle, Stephen A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer |
title | A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer |
title_full | A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer |
title_fullStr | A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer |
title_full_unstemmed | A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer |
title_short | A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer |
title_sort | g-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468576/ https://www.ncbi.nlm.nih.gov/pubmed/26077929 http://dx.doi.org/10.1038/srep11385 |
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