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

Investor logo
Investor logo

Warning

This publication doesn't include Faculty of Education. It includes Central European Institute of Technology. Official publication website can be found on muni.cz.
Authors

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 Jiří ISLAM Barira PEDLEY R. Barbara HARTLEY John A. NEIDLE Stephen

Year of publication 2015
Type Article in Periodical
Magazine / Source Scientific Reports
MU Faculty or unit

Central European Institute of Technology

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.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.