ArticlePloS one2015
Targeting KRAS Oncogene in Colon Cancer Cells with 7-Carboxylate Indolo[3,2-b]quinoline Tri-Alkylamine Derivatives.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 46 citations in OpenAlex.
- Thiazole peptidomimetics as chemical modulators ofRSC chemical biology · 2025Article
- Structure-activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling.Scientific reports · 2024Article
- Application of G-quadruplex targets in gastrointestinal cancers: Advancements, challenges and prospects.World journal of gastrointestinal oncology · 2023Review
- Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole.Pharmaceutics · 2022Article
- Arene Ru(II) Complexes Acted as PotentialMolecules (Basel, Switzerland) · 2022Article
- c-Myc Protein Level Affected by Unsymmetrical Bisacridines Influences Apoptosis and Senescence Induced in HCT116 Colorectal and H460 Lung Cancer Cells.International journal of molecular sciences · 2022Article
- Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy.Journal of personalized medicine · 2022Review
- Major Achievements in the Design of Quadruplex-Interactive Small Molecules.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids.Pharmaceuticals (Basel, Switzerland) · 2021Article
- The Prognostic Value ofMolecular imaging and radionuclide therapy · 2020Article
- Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation.Cancers · 2020Article
- Article
- Characterization of G-Quadruplex Motifs in espB, espK, and cyp51 Genes of Mycobacterium tuberculosis as Potential Drug Targets.Molecular therapy. Nucleic acids · 2019Article
- Mangrove derived Streptomyces sp. MUM265 as a potential source of antioxidant and anticolon-cancer agents.BMC microbiology · 2019Article
- Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex.Nature communications · 2018Article
- Characterization of clinically used oral antiseptics as quadruplex-binding ligands.Nucleic acids research · 2018Article
- Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities.Journal of experimental & clinical cancer research : CR · 2018Review
- High-resolution three-dimensional NMR structure of theThe Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundA guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-quadruplex structure (G4), which has an important role in the regulation of KRAS transcription. We have previously identified indolo[3,2-b]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads. Herein we investigated the anticancer mechanism of action of these compounds, which we hypothesized due to stabilization of the G4 sequence in the KRAS promoter and subsequent down-regulation of gene expression. METHODOLOGY/PRINCIPAL
findingsIQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced KRAS promoter activity in a dual luciferase reporter assay. Moreover, IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells (IC50 < 2.69 μM), without eliciting cell death in non-malignant HEK293T human embryonic kidney, and human colon fibroblasts CCD18co. IQ3A compounds significantly reduced KRAS mRNA and protein steady-state levels at IC50 concentrations, and increased p53 protein steady-state levels and cell death by apoptosis in HCT116 cells (mut KRAS, wt p53). Furthermore, KRAS silencing in HCT116 p53 wild-type (p53(+/+)) and null (p53(-/-)) isogenic cell lines induced a higher level of cell death, and a higher IQ3A-induced cell death in HCT116 p53(+/+) compared to HCT116 p53(-/-).
conclusionsHerein we provide evidence that G4 ligands such as IQ3A compounds can target G4 motifs present in KRAS promoter, down-regulate the expression of the mutant KRAS gene through inhibition of transcription and translation, and induce cell death by apoptosis in colon cancer cell lines. Thus, targeting KRAS at the genomic level with G4 ligands may be a new anticancer therapy strategy for colon cancer.
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