Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jul 3;135(26):9640-3.
doi: 10.1021/ja404868t. Epub 2013 Jun 25.

G-quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells

Affiliations

G-quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells

Keith I E McLuckie et al. J Am Chem Soc. .

Abstract

Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Synthetic lethality can also be achieved "chemically" by combination of drug-like molecules targeting distinct but cooperative pathways. Previously, we reported that the small molecule pyridostatin (PDS) stabilizes G-quadruplexes (G4s) in cells and elicits a DNA damage response by causing the formation of DNA double strand breaks (DSB). Cell death mediated by ligand-induced G4 stabilization can be potentiated in cells deficient in DNA damage repair genes. Here, we demonstrate that PDS acts synergistically both with NU7441, an inhibitor of the DNA-PK kinase crucial for nonhomologous end joining repair of DNA DSBs, and BRCA2-deficient cells that are genetically impaired in homologous recombination-mediated DSB repair. G4 targeting ligands have potential as cancer therapeutic agents, acting synergistically with inhibition or mutation of the DNA damage repair machinery.

PubMed Disclaimer

Figures

Figure 1
Figure 1
(A) Structures of pyridostatins: PDS, PDSI and PDSK. (B) Growth inhibition by PDS molecules in HT1080 cells (GI50 in μM). **P = 0.006, 1 way ANOVA. (C) Structure of DNA-PKcs inhibitor NU7441.
Figure 2
Figure 2
Synergistic growth inhibition of cancer cells using PDSI and NU7441. (A) 3D response surface for the combination of PDSI with NU7441 in HT1080 cells. (B) Nuclear 53BP1 and (C) RAD51 in HT1080 cells treated with PDSI (2 μM) and NU7441 (300 nM) for 24 h. Error bars indicate SEM. (D) Growth inhibition by PDSI and NU7441 in isogenic HCT116 WT or BRCA2–/– cancer cells. Binary treatment was NU7441 (1 μM) with a range of PDSI concentrations (binary GI50). All GI50 data quoted in μM. Significance compared to PDSI (unpaired t test, one tail, *P < 0.05, **P < 0.01). (E,F) 3D response surfaces for the combination of PDSI with NU7441 in HCT116 WT cells or BRCA2–/– cells. (G) Nuclear 53BP1 and (H) RAD51 in HCT116 WT and BRCA2–/– cells treated with PDSI (2 μM) and NU7441 (150 nM) for 24 h. Dashed lines in C/H denote level of additive response. Details of statistical significance between pair wise combinations, for panels B, C, G, and H is illustrated in Table S3. Data in Panels A, E, and F were measured using an end point luminescence assay. Data in panel D were measured by continuous cell monitoring.

References

    1. Davis J. Angew. Chem., Int. Ed. 2004, 43, 668. - PubMed
    1. Bochman M. L.; Paeschke K.; Zakian V. A. Nat. Rev. Genet. 2012, 13, 770. - PMC - PubMed
    2. Di Antonio M.; Rodriguez R.; Balasubramanian S. Methods 2012, 57, 84–92. - PMC - PubMed
    3. Bugaut A.; Balsubramanian S. Nucleic Acids Res. 2012, 40, 4727. - PMC - PubMed
    4. Siddiqui-Jain A.; Grand C. L.; Bearss D. J.; Hurley L. H. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 11593. - PMC - PubMed
    5. Rankin S.; Reszka A. P.; Huppert J.; Zloh M.; Parkinson G. N.; Todd A. K.; Ladame S.; Balasubramanian S.; Neidle S. J. Am. Chem. Soc. 2005, 127, 10584. - PMC - PubMed
    6. Cogoi S.; Xodo L. E. Nucleic Acids Res. 2006, 34, 2536. - PMC - PubMed
    7. Kumari S.; Bugaut A.; Huppert J. L.; Balasubramanian S. Nat. Chem. Biol. 2007, 3, 218. - PMC - PubMed
    1. Huppert J. L.; Balasubramanian S. Nucleic Acids Res. 2005, 33, 2908. - PMC - PubMed
    2. Todd A. K.; Johnston M.; Neidle S. Nucleic Acids Res. 2005, 33, 2901. - PMC - PubMed
    1. Huppert J. L.; Balasubramanian S. Nucleic Acids Res. 2007, 35, 406. - PMC - PubMed
    1. Schaffitzel C.; Berger I.; Postberg J.; Hanes J.; Lipps H. J.; Pluckthun A. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 8572. - PMC - PubMed

Publication types

MeSH terms