A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Ohnmacht, Stephan A ^a   Marchetti, Chiara ^a   Gunaratnam, Mekala ^a   Besser, Rachael J ^a   Haider, Shozeb M ^a   Di Vita, Gloria ^a   Lowe, Helen L ^b   Mellinas Gomez, Maria ^b   Diocou, Seckou ^b   Robson, Mathew ^b   Šponer, Jiri ^c,d   Islam, Barira ^c   Barbara Pedley, R ^b   Hartley, John A ^b   Neidle, Stephen ^a  

^a UNIVERSITY OF LONDON   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c CENTRAL EUROPEAN INSTITUTE OF TECHNOLOGY   (Czech Republic)

^d INSTITUTE OF BIOPHYSICS   (Czech Republic)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BCL2 PROTEIN, MOUSE; GUANINE QUADRUPLEX; IMIDE; KRAS2 PROTEIN, MOUSE; NAPHTHALENE DERIVATIVE; NAPHTHALENEDIIMIDE; PROTEIN BCL 2; PROTEIN P21;

ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG ADMINISTRATION; DRUG EFFECTS; DRUG SCREENING; FEMALE; GENE EXPRESSION; GENETIC TRANSCRIPTION; GENETICS; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; METABOLISM; MOLECULAR DYNAMICS; MOUSE; NUDE MOUSE; PANCREATIC NEOPLASMS; PATHOLOGY; PROMOTER REGION; TUMOR CELL LINE; TUMOR VOLUME;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; DRUG ADMINISTRATION SCHEDULE; FEMALE; G-QUADRUPLEXES; GENE EXPRESSION; HUMANS; IMIDES; INJECTIONS, INTRAVENOUS; MICE; MICE, NUDE; MOLECULAR DYNAMICS SIMULATION; NAPHTHALENES; PANCREATIC NEOPLASMS; PROMOTER REGIONS, GENETIC; PROTO-ONCOGENE PROTEINS C-BCL-2; PROTO-ONCOGENE PROTEINS P21(RAS); TRANSCRIPTION, GENETIC; TUMOR BURDEN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84935920509     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep11385     Document Type: Article

References (60)

1. Vincent, A., Herman, J., Schulick, R., Hruban, R. H. & Goggins, M. Pancreatic cancer. Lancet 378, 607-620 (2011).
2. Matthaei, H., Semaan. A. & Hruban, R. H. The genetic classification of pancreatic neoplasia. J. Gastroenterol. (2015) DOI: 10.1007/s00535-015-1037-4.
3. http://www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics. Date of access 06/02/2015.
4. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/pancreas/incidence/uk-pancreatic-cancer-incidence-statistics. Date of access 06/02/2015.
5. Sant, M. et al. EUROCARE-4. Survival of cancer patients diagnosed in 1995-1999. Results and commentary. Eur. J. Cancer 45, 931-991 (2009).
6. Carmichael, J. et al. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Brit. J. Cancer 73, 101-105 (1996).
7. Slusarczyk, M. et al. Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. J. Med. Chem. 57, 1531-1542 (2014).
8. Courtin, A. et al. Anti-tumour efficacy of capecitabine in a genetically engineered mouse model of pancreatic cancer. PLoS One 8, e67330 (2013).
9. Borazanci, E. & Von Hoff, D. D. Nab-paclitaxel and gemcitabine for the treatment of patients with metastatic pancreatic cancer. Expert Rev. Gastroenterol. Hepatol. 8, 739-747 (2014).
10. Burge, S., Parkinson, G. N., Hazel, P., Todd, A. K. & Neidle, S. Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 34, 5402-5415 (2006).
11. Todd, A. K., Johnston, M. & Neidle, S. Highly prevalent putative quadruplex sequence motifs in human DNA. Nucleic Acids Res. 33, 2901-2907 (2005).
12. Huppert, J. L. & Balasubramanian, S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 33, 2908-2916 (2005).
13. Huppert, J. L. & Balasubramanian, S. G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res. 35, 406-413 (2007).
14. Bugaut, A. & Balasubramanian, S. 5'-UTR RNA G-quadruplexes: translation regulation and targeting. Nucleic Acids Res. 40, 4727-4741 (2012).
15. Nambiar, M., Srivastava, M., Gopalakrishnan, V., Sankaran, S. K. & Raghavan, S. C. G-quadruplex structures formed at the HOX11 breakpoint region contribute to its fragility during t(10;14) translocation in T-cell leukemia. Mol. Cell. Biol. 33, 4266-4281 (2013).
16. Dong, D. W. et al. Association of G-quadruplex forming sequences with human mtDNA deletion breakpoints. BMC Genomics 15, 677 (2014).
17. Biffi, G., Tannahill, D., McCafferty, J. & Balasubramanian, S. Quantitative visualization of DNA G-quadruplex structures in human cells. Nat. Chem. 5, 182-186 (2013).
18. Henderson, A. et al. Detection of G-quadruplex DNA in mammalian cells. Nucleic Acids Res. 42, 860-869 (2013).
19. Biffi, G., Tannahill, D., Miller, J., Howat, W. J. & Balasubramanian, S. Elevated levels of G-quadruplex formation in human stomach and liver cancer tissues. PLoS One 9, e102711 (2014).
20. Siddiqui-Jain, A., Grand, C. L., Bearss, D. J. & Hurley, L. H. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc. Natl. Acad. Sci. USA 99, 11593-11598 (2002).
21. Balasubramanian, S., Hurley, L. H. & Neidle, S. Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat. Rev. Drug Discov. 10, 261-275 (2011).
22. Cuenca, F. et al. Tri-and tetra-substituted naphthalene diimides as potent G-quadruplex ligands. Bioorg. Med. Chem. Lett. 18, 1668-1673 (2008).
23. Gunaratnam, M., Cuenca, F. & Neidle, S, inventors; University College London, assignee. Naphthalene diimide compounds interacting with G-quadruplex regions in DNA. US patent 8796456, 2014 August 14, European patent 2227470, 2104 March 5, Japanese patent 5366968, 2013 August 29.
24. Gunaratnam, M. et al. Targeting human gastrointestinal stromal tumour cells with a quadruplex-binding small molecule. J. Med. Chem. 52, 3774-3783 (2009).
25. Hampel, S. M., Sidibe, A., Gunaratnam, M., Riou, J.-F. & Neidle, S. Tetrasubstituted naphthalene diimide ligands with selectivity for telomeric G-quadruplexes and cancer cells. Bioorg. Med. Chem. Lett. 20, 6459-6463 (2010).
26. Gunaratnam, M. et al. Targeting pancreatic cancer with a G-quadruplex ligand. Bioorg. Med. Chem. 19, 7151-7157 (2011).
27. Collie, G. W. et al. Structural basis for telomeric G-quadruplex naphthalene diimide ligand targeting J. Am. Chem. Soc. 134, 2723-2731 (2012).
28. Micco, M. et al. Structure-based design and evaluation of naphthalene diimide G-quadruplex ligands as telomere targeting agents in pancreatic cancer cells. J. Med. Chem. 56, 2959-2974 (2013).
29. Dai, J., Chen, D., Jones, R. A., Hurley, L. H. & Yang, D. NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region. Nucleic Acids Res. 34, 5133-5144 (2006).
30. Agrawal, P., Lin, C., Mathad, R. I., Carver, M. & Yang, D. The major G-quadruplex formed in the human BCL-2 proximal promoter adopts a parallel structure with a 13-nt loop in K+ solution. J. Amer. Chem. Soc. 136, 1750-1753 (2014).
31. Shahid, R., Bugaut, A. & Balasubramanian, S. The BCL-2 5' untranslated region contains an RNA G-quadruplex-forming motif that modulates protein expression. Biochemistry 49, 8300-8306 (2010).
32. Wang, X. D. et al. Turning off transcription of the bcl-2 gene by stabilizing the bcl-2 promoter quadruplex with quindoline derivatives. J. Med. Chem. 53, 4390-4398 (2010).
33. Wang, C. et al. Ruthenium (II) polypyridyl complexes stabilize the bcl-2 promoter quadruplex and induce apoptosis of Hela tumor cells. Biometals 26, 387-402 (2013).
34. Kendrick, S. et al. The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure. J. Amer. Chem. Soc. 136, 4161-4171 (2014).
35. Perez, A. et al. Refinement of the AMBER force field for nucleic acids: improving the description of alpha/gamma conformers. Biophys. J. 92, 3817-3829 (2007).
36. Krepl, M. et al. Reference simulations of noncanonical nucleic acids with different chi variants of the AMBER force field: quadruplex DNA, quadruplex RNA and Z-DNA. J. Chem. Theory Comput. 8, 2506-2520 (2012).
37. Reed, J. E. et al. TRAP-LIG, a modified TRAP assay to quantitate telomerase inhibition by small molecules. Anal. Biochem. 380, 99-105 (2008).
38. Burger, A. M. et al. A G-quadruplex binding telomerase inhibitor with in vivo anticancer activity. Cancer Res. 65, 1489-1496 (2005).
39. Salvati, E. et al. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. J. Clin. Invest. 117, 3236-3247 (2007).
40. Rodriguez, R. et al. Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat. Chem. Biol. 8, 301-310 (2012).
41. Muller, S. et al. Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells. Org. Biomol. Chem. 10, 6537-6546 (2012).
42. Campani, D. et al. Bcl-2 expression in pancreas development and pancreatic cancer progression. J. Pathol. 194, 444-450 (2001).
43. Huang, S., Okumura, K. & Sinicrope, F. A. BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin. Cancer Res. 15, 150-159 (2009).
44. Yuan, Y. et al. Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells. Cell Death Dis. 4, e690 (2013).
45. Ocker, M. et al. Variants of bcl-2 specific siRNA for silencing antiapoptotic bcl-2 in pancreatic cancer. Gut 54, 1298-1308 (2005).
46. Sun, H. et al. A newly identified G-quadruplex as a potential target regulating Bcl-2 expression. Biochim. Biophys. Acta 184D, 3052-3057 (2014).
47. Prato, G., Silvent, S., Saka, S., Lamberto, M. & Kosenkov, D. Thermodynamics of binding of di-and tetrasubstituted naphthalene diimide ligands to DNA G-quadruplex. J. Phys. Chem. (2015). DOI: 10.1021/jp509637y.
48. Nadai, M. et al. Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells. Int. J. Oncol. 46, 369-380 (2015).
49. Guyen, B., Schultes, C. M., Hazel, P., Mann, J. & Neidle, S. Synthesis and evaluation of analogues of 10H-indolo[3,2-b]quinoline as G-quadruplex stabilising ligands and potential inhibitors of the enzyme telomerase. Org. Biomol. Chem. 2, 981-988 (2004).
50. Stadlbauer, P., Krepl, M., Cheatham, T. E., Koča, J. & Šponer, J. Structural dynamics of possible late-stage intermediates in folding of quadruplex DNA studied by molecular simulations. Nucleic Acids Res. 41, 7128-7143 (2013).
51. Cornell, W. D. et al. A 2nd generation force-field for the simulation of proteins, nucleic acids and organic-molecules. J. Amer. Chem. Soc. 117, 5179-5197 (1995).
52. Joung, I. S. & Cheatham, T. E. Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations. J. Phys. Chem. B112, 9020-9041 (2008).
53. Harvey, M.J., Giupponi, G. & Fabritiis, G. D. ACEMD: Accelerating biomolecular dynamics in the microsecond time scale. J. Chem. Theory Comp. 5, 1632-1639 (2009).
54. Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: An Nlog(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089-10092 (1993).
55. Ryckaert, J.-P., Ciccotti, G. & Berendsen, H. J. C. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comp. Phys. 23, 327-341 (1977).
56. Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A. & Haak, J. R. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684-3690 (1984).
57. Roe, D. R. & Cheatham, T. E. PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comp. 9, 3084-3095 (2013).
58. Humphrey, W., Dalke, A. & Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graphics 14, 33-38 (1996).
59. Workman, P. et al. Guidelines for the welfare and use of animals in cancer research. Br. J. Cancer 102, 1555-1577 (2010).
60. Tomayko, M. M. & Reynolds, C. P. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother. Pharmacol. 24, 148- 154 (1989).