title: A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer.
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.
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Ohnmacht
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
authors.forename: Mekala
authors.initials: M
authors.lastname: Gunaratnam
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
authors.forename: Rachael J
authors.initials: RJ
authors.lastname: Besser
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
authors.forename: Shozeb M
authors.initials: SM
authors.lastname: Haider
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
authors.forename: Gloria
authors.initials: G
authors.lastname: Di Vita
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Lowe
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Mellinas-Gomez
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Seckou
authors.initials: S
authors.lastname: Diocou
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Mathew
authors.initials: M
authors.lastname: Robson
authors.affiliation: 1] Central European Institute of Technology (CEITEC), Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic [2] Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Šponer
authors.affiliation: Central European Institute of Technology (CEITEC), Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic.
authors.forename: Barira
authors.initials: B
authors.lastname: Islam
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: R Barbara
authors.initials: RB
authors.lastname: Pedley
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.affiliation: UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D005260:Female; D054856:G-Quadruplexes; D015870:Gene Expression; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007094:Imides; D009281:Naphthalenes; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; C542131:naphthalenediimide; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)