1. Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule
- Author
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Marchetti, Chiara, Zyner, Katherine G, Ohnmacht, Stephan A, Robson, Mathew, Haider, Shozeb M, Morton, Jennifer P, Marsico, Giovanni, Vo, Tam, Laughlin-Toth, Sarah, Ahmed, Ahmed A, Di Vita, Gloria, Pazitna, Ingrida, Gunaratnam, Mekala, Besser, Rachael J, Andrade, Ana CG, Diocou, Seckou, Pike, Jeremy A, Tannahill, David, Pedley, R Barbara, Evans, TR Jeffry, Wilson, W David, Balasubramanian, Shankar, and Neidle, Stephen
- Subjects
Antimetabolites, Antineoplastic ,endocrine system diseases ,Computational Biology ,Down-Regulation ,Mice, Nude ,Antineoplastic Agents ,Deoxycytidine ,Xenograft Model Antitumor Assays ,Gemcitabine ,digestive system diseases ,3. Good health ,G-Quadruplexes ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Mice ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Drug Design ,Animals ,Humans ,Computer Simulation ,Carcinoma, Pancreatic Ductal ,DNA Damage - Abstract
Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[ lmn][3,8]phenanthroline-1,3,6,8(2 H,7 H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.