Targeting KRAS Oncogene in Colon Cancer Cells with 7-Carboxylate Indolo[3,2-b]quinoline Tri-Alkylamine Derivatives

A 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 cha...

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Published in:PloS one 2015-05, Vol.10 (5), p.e0126891-e0126891
Main Authors: Brito, Hugo, Martins, Ana Cláudia, Lavrado, João, Mendes, Eduarda, Francisco, Ana Paula, Santos, Sofia A, Ohnmacht, Stephan A, Kim, Nam-Soon, Rodrigues, Cecília M P, Moreira, Rui, Neidle, Stephen, Borralho, Pedro M, Paulo, Alexandra
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Biotechnology
Cancer
Cancer cells
Cancer genetics
Cell death
Cell growth
Cell Line, Tumor
Cell Proliferation - drug effects
Chemistry
Colon
Colon cancer
Colonic Neoplasms - drug therapy
Colonic Neoplasms - genetics
Colorectal cancer
Comparative analysis
Deoxyribonucleic acid
DNA
Fibroblasts
G-Quadruplexes - drug effects
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Gene regulation
Genes, ras
Genetic aspects
Guanine
HCT116 Cells
HEK293 Cells
Humans
K-Ras protein
Ligands
Molecular structure
Mortality
Mutation
Oncogenes
Organic compounds
p53 Protein
Pharmaceutical sciences
Pharmacy
Promoter Regions, Genetic
Proteins
Purines
Quinoline
Quinolines
Quinolines - chemistry
Quinolines - pharmacology
RNA
Stabilization
Steady state
Telomerase
Transcription
Transcription (Genetics)
Tumor cell lines
Tumor proteins
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Summary:A 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. IQ3A 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(-/-). Herein 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0126891