A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

Stephan A. Ohnmacht, Chiara Marchetti, Mekala Gunaratnam, Rachael J. Besser, Shozeb M. Haider, Gloria Di Vita, Helen L. Lowe, Maria Mellinas-Gomez, Seckou Diocou, Mathew Robson, Jiri Šponer, Barira Islam, R. Barbara Pedley, John A. Hartley, Stephen Neidle

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

LanguageEnglish
Article number11385
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 16 Jun 2015
Externally publishedYes

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G-Quadruplexes
Pancreatic Neoplasms
Neoplasms
Genes
Cell Nucleus
Heterografts
Genetic Promoter Regions
Down-Regulation
Growth

Cite this

Ohnmacht, S. A., Marchetti, C., Gunaratnam, M., Besser, R. J., Haider, S. M., Di Vita, G., ... Neidle, S. (2015). A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer. Scientific Reports, 5, [11385]. https://doi.org/10.1038/srep11385
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. In: Scientific Reports. 2015 ; Vol. 5.
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abstract = "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.",
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Ohnmacht, SA, Marchetti, C, Gunaratnam, M, Besser, RJ, Haider, SM, Di Vita, G, Lowe, HL, Mellinas-Gomez, M, Diocou, S, Robson, M, Šponer, J, Islam, B, Barbara Pedley, R, Hartley, JA & Neidle, S 2015, 'A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer', Scientific Reports, vol. 5, 11385. https://doi.org/10.1038/srep11385

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.

In: Scientific Reports, Vol. 5, 11385, 16.06.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

AU - Ohnmacht, Stephan A.

AU - Marchetti, Chiara

AU - Gunaratnam, Mekala

AU - Besser, Rachael J.

AU - Haider, Shozeb M.

AU - Di Vita, Gloria

AU - Lowe, Helen L.

AU - Mellinas-Gomez, Maria

AU - Diocou, Seckou

AU - Robson, Mathew

AU - Šponer, Jiri

AU - Islam, Barira

AU - Barbara Pedley, R.

AU - Hartley, John A.

AU - Neidle, Stephen

PY - 2015/6/16

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N2 - 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.

AB - 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.

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SN - 2045-2322

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Ohnmacht SA, Marchetti C, Gunaratnam M, Besser RJ, Haider SM, Di Vita G et al. A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer. Scientific Reports. 2015 Jun 16;5. 11385. https://doi.org/10.1038/srep11385