A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer
| Authors | |
|---|---|
| Year of publication | 2015 |
| Type | Article in Periodical |
| Magazine / Source | Scientific Reports |
| MU Faculty or unit | |
| Citation | |
| Web | http://www.nature.com/srep/2015/150616/srep11385/pdf/srep11385.pdf |
| Doi | http://dx.doi.org/10.1038/srep11385 |
| Field | Biophysics |
| Keywords | NAPHTHALENE DIIMIDE LIGANDS; AMBER FORCE-FIELD; DNA G-QUADRUPLEX; MOLECULAR-DYNAMICS; NUCLEIC-ACIDS; TUMOR-CELLS; BCL-2 EXPRESSION; PROMOTER REGION; HUMAN GENOME; GEMCITABINE |
| Attached files | |
| 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 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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