PloS one, 2016-04, Vol.11 (4), p.e0153155
2016
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- Autor(en) / Beteiligte
- Titel
- Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway
- Ist Teil von
- PloS one, 2016-04, Vol.11 (4), p.e0153155
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2016
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0153155Titel-ID: cdi_plos_journals_1782830051
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, AKT protein, AKT2 protein, Angiogenesis, Antifungal agents, Apoptosis, Apoptosis - drug effects, Bcl-2 protein, Biology, Biology and Life Sciences, Breast cancer, Cancer, Carcinogenesis, Carcinogens, Care and treatment, Caspase-3, Caspases - metabolism, Cell cycle, Cell Line, Tumor, Cellular signal transduction, Chemistry, Chemokine CXCL12 - antagonists & inhibitors, College campuses, CXCL12 protein, Cyclin D1, Cytotoxicity, Down-Regulation - drug effects, Drug therapy, Enzyme Activation - drug effects, G1 Phase - drug effects, Genetic aspects, Growth factors, Health aspects, Humans, Imidazoles, Imidazoles - chemistry, Imidazoles - metabolism, Imidazoles - pharmacology, Informatics, Kinases, Laboratories, Lead, Liver cancer, Medicine, Medicine and Health Sciences, Molecular docking, Molecular Docking Simulation, Neoplasm Invasiveness, Pharmaceutical sciences, Pharmacology, Phosphatidylinositol 3-Kinases - metabolism, Phosphorylation, Phosphorylation - drug effects, Physical Sciences, Physiological aspects, Poly(ADP-ribose) polymerase, Protein kinase, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins c-akt - chemistry, Proto-Oncogene Proteins c-akt - metabolism, Pyridines, Rodents, Signal transduction, Signal Transduction - drug effects, Signaling, Studies, Survivin, Synthesis, Threonine, TOR protein, TOR Serine-Threonine Kinases - metabolism, Vascular endothelial growth factor