Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep11385
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Funding
- Pancreatic Cancer Research Fund
- Medical Research Council
- Cancer Research UK [C2259/A16569]
- Grant Agency of the Czech Republic [P208/11/1822]
- project CEITEC, Central European Institute of Technology from European Regional Development Fund [CZ.1.05/1.1.00/02.0068]
- project Employment of Best Young Scientists for International Cooperation Empowerment [CZ.1.07/2.3.00/30.0037]
- European Social Fund
- state budget of the Czech Republic
- Cancer Research UK [16569, 21030, 16463] Funding Source: researchfish
- Medical Research Council [MC_PC_12024, G1001497] Funding Source: researchfish
- MRC [G1001497, MC_PC_12024] Funding Source: UKRI
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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 tumourbearing 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 quadruplexinteractive 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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