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A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer
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A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer
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Journal Article
A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer
2015
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 14
/ 14/19
/ 14/34
/ 59/5
/ 64/60
/ Animals
/ Antineoplastic Agents - chemistry
/ Antineoplastic Agents - pharmacology
/ Drug Administration Schedule
/ Female
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Molecular Dynamics Simulation
/ Nuclei
/ Pancreatic Neoplasms - drug therapy
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Pancreatic Neoplasms - pathology
/ Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
/ Proto-Oncogene Proteins c-bcl-2 - chemistry
/ Proto-Oncogene Proteins c-bcl-2 - genetics
/ Proto-Oncogene Proteins c-bcl-2 - metabolism
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Proto-Oncogene Proteins p21(ras) - metabolism
/ Science
/ Tumors
