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: Stephan A Ohnmacht, Chiara Marchetti, Mekala Gunaratnam, Rachael J Besser, Shozeb M Haider, Gloria Di Vita, Helen L Lowe, Maria Mellinas-Gomez, Seckou Diocou, Mathew Robson, Jiri Šponer, Barira Islam, R Barbara Pedley, John A Hartley, Stephen Neidle
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 11385 (Jun 16 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26077929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Imides
• Naphthalenes
• Proto-Oncogene Proteins c-bcl-2
• Bcl2 protein, mouse
• naphthalenediimide
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Drug Administration Schedule
• Female
• G-Quadruplexes
• Gene Expression
• Humans
• Imides (chemistry, pharmacology)
• Injections, Intravenous
• Mice
• Mice, Nude
• Molecular Dynamics Simulation
• Naphthalenes (chemistry, pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, chemistry, genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Transcription, Genetic
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays