Therapeutic Uses of Peptide Nucleic Acids (PNA) in Oncology

  • Nadia Zaffaroni
  • Raffaella Villa
  • Marco Folini
Part of the Medical Intelligence Unit book series (MIUN)


Peptide nucleic acids (PNAs) are DNA mimics in which the sugar-phosphate backbone has been replaced by an uncharged backbone based on amino acids. Due to their ability to bind to complementary polynucleotides, PNAs have been successfully used to inhibit transcription and/or translation of genes able to confer a survival advantage to cancer cells, such as c-myc and bcl-2. PNAs targeted to the RNA template region of telomerase have also been used to inhibit the catalytic activity of this enzyme, which is responsible for the immortalized phenotype of a large majority of tumor cells. Because it is thought that naked PNAs are not taken up spontaneously by most cells, a number of delivery strategies have been developed including the use of so-called “cell-penetrating peptides”. Chimeric molecules made by coupling PNAs with such peptides have been shown to accumulate inside tumor cells to an extent sufficient to guarantee the biological effect of PNAs. Overall, these results indicate that PNAs may be useful tools for target-directed anticancer therapeutic interventions.


Melanoma Cell Peptide Nucleic Acid Telomeric Repeat Amplification Protocol Telomeric Repeat Amplification Protocol Hammerhead Ribozyme 
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  1. 1.
    Bronson SK, Smithies O. Altering mice by homologous recombination using embryonic stem cells. J Biol Chem 1994; 269:27155–27158.PubMedGoogle Scholar
  2. 2.
    Maher Jr L. Prospects for the therapeutic use of antigene oligonucleotides. Cancer Invest 1996; 14:66–82.PubMedGoogle Scholar
  3. 3.
    Crooke ST. Molecular mechanisms of action of antisense drug. Biochim Biophys Acta 1999; 1489:31–44.PubMedGoogle Scholar
  4. 4.
    Manoharan M. 2′-carbohydrate modifications in antisense oligonucleotide therapy: Importance of conformation, configuration and conjugation. Biochim Biophys Acta 1999; 1489:117–130.PubMedGoogle Scholar
  5. 5.
    Miller PS. Oligonucleotide methylphosphonates as antisense reagents. Biotechnology 1991; 9:358–362.PubMedCrossRefGoogle Scholar
  6. 6.
    Summerton J, Weller D. Morpholino antisense oligomers: Design, preparation, and properties. Antisense Nucleic Acid Drug Dev 1997; 7:187–195.PubMedGoogle Scholar
  7. 7.
    Nielsen PE, Eghlm M, Berg RH et al. Sequence selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 1991; 254:1497–1500.PubMedCrossRefGoogle Scholar
  8. 8.
    Egholm M, Buchardt O, Christensen L et al. PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules. Nature 1993; 365:566–568.PubMedCrossRefGoogle Scholar
  9. 9.
    Smulevitch SV, Simmons CG, Norton JC et al. Enhancement of strand invasion by oligonucleotides through manipulation of backbone charge, Nat Biotechnol 1996; 14:1700–1704.PubMedCrossRefGoogle Scholar
  10. 10.
    Demidov VV, Potaman VN, Frank-Kamenetskii MD et al. Biochem Pharmacol 1994; 48:1310–1313.PubMedCrossRefGoogle Scholar
  11. 11.
    Mologni L, Nielsen PE, Gambacorti-Passerini C. In vitro transcriptional and translational block of the bcl-2 gene operated by peptide nucleic acid. Biochem Biophys Res Commun 1999; 264:57–543.CrossRefGoogle Scholar
  12. 12.
    Boffa LC, Scarfi S, Mariani MR et al. Dihydrotestosterone as a selective cellular/nuclear localization vector for anti-gene peptide nucleic acid in prostatic carcinoma cells. Cancer Res 2000; 60:2258–2262.PubMedGoogle Scholar
  13. 13.
    Cutrona G, Carpaneto E, Ulivi M et al. Effects in live cells of a c-myc anti-gene PNA linked to a nuclear localization signal. Nat Biotechnol 2000; 18:300–303.PubMedCrossRefGoogle Scholar
  14. 14.
    Knudsen H, Nielsen PE. Antisense properties of duplex-and triplex-forming PNAs. Nucleic Acids Res 1996; 24:494–500.PubMedCrossRefGoogle Scholar
  15. 15.
    Norton JC, Piatyszek MA, Wright WE et al. Inhibition of human telomerase by peptide nucleic acids. Nat Biotechnol 1996; 14:615–619.PubMedCrossRefGoogle Scholar
  16. 16.
    Villa R, Folini M, Lualdi S et al. Inhibition of telomerase activity by a cell-penetrating peptide nucleic acid construct inhuman melanoma cells. FEBS Lett 2000; 473:241–248.PubMedCrossRefGoogle Scholar
  17. 17.
    Mollegaard NE, Buchardt O, Egholm M et al. Peptide nucleic acid. DNA strand displacement loops as artificial transcription promoters. Proc Nat Acad Sci USA 1994; 91:3892–3895.PubMedCrossRefGoogle Scholar
  18. 18.
    Wang G, Xu X, Pace B et al. Peptide nucleic acid (PNA) binding-mediated induction of human γ-globin gene expression. Nucleic Acids Res 1999; 27:2806–2813.PubMedCrossRefGoogle Scholar
  19. 19.
    Wittung P, Kajanus J, Edwards K et al. Phospholipidic membrane permeability of peptide nucleic acid. FEBS Lett 1995; 365:27–29.PubMedCrossRefGoogle Scholar
  20. 20.
    Tyler BM, McCormick DJ, Hostall CV et al. Specific gene blockade shows that peptide nucleic acids readily enter neuronal cells in vivo. FEBS Lett 1998; 421:280–284.PubMedCrossRefGoogle Scholar
  21. 21.
    Schwarze SR, Hruska KA, Dowdy SF. Protein transduction: Unrestricted delivery into all cells? Trends Cell Biol 2000; 10:290–295.PubMedCrossRefGoogle Scholar
  22. 22.
    Lindgren M, Hallbrink M, Prochiantz A et al. Cell-penetrating peptides. Trends Pharm Sci 2000; 21:99–103.PubMedCrossRefGoogle Scholar
  23. 23.
    Hawiger J. Noninvasive intracellular delivery of functional peptides and proteins. Curr Opin Chem Biol 1999; 3:89–94.PubMedCrossRefGoogle Scholar
  24. 24.
    Pooga M, Soomets U, Hallbrink M et al. Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat Biotechnol 1998; 16:857–861.PubMedCrossRefGoogle Scholar
  25. 25.
    Ljungstrom T, Knudsen H, Nielsen PE. Cellular uptake of adamantyl conjugated peptide nucleic acids. Bioconjug Chem 1999; 10:965–972.PubMedCrossRefGoogle Scholar
  26. 26.
    Uhlmann E. Peptide nucleic acids (PNA) and PNA-DNA chimeras: From high binding affinity towards biological function. Biol Chem 1998; 379:1045–1052.PubMedGoogle Scholar
  27. 27.
    Adams JM, Cory S. The Bcl-2 protein family: Arbiters of cell survival. Science 1998; 281:1322–1326.PubMedCrossRefGoogle Scholar
  28. 28.
    Reed JC. Regulation of apoptosis by bcl-2 family and its role in cancer and chemoresistance. Curr Opin Oncol 1995; 7:541–546.PubMedGoogle Scholar
  29. 29.
    Reed JC, Stein C, Subasinghe C et al. Antisense-mediated inhibition of BCL2 protooncogene expression and keukemic cell growthand survival: Comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides. Cancer Res 1990; 50:6565–6570.PubMedGoogle Scholar
  30. 30.
    Jansen B, Wacheck V, Heere-Ress E et al. Chemosensitisation of malignant melanoma to BCL2 antisense therapy. Lancet 2000; 356:1728–1733.PubMedCrossRefGoogle Scholar
  31. 31.
    Elend M, Eilers M. Cell growth: Downstream of Myc-to grow or to cycle?. Curr Biol 1999; 9:R936–938.PubMedCrossRefGoogle Scholar
  32. 32.
    Fuhrmann G, Rosemberg G, Grusch M et al. The MYC dualism in growth and death. Mutat Res 1999; 437:205–217.PubMedCrossRefGoogle Scholar
  33. 33.
    Catapano CV, McGuffie EM, Pacheco D et al. Inhibition of gene expression and proliferation by triple helix-forming oligonucleotides directed to the c-myc gene. Biochemistry 2000; 39:5126–5138.PubMedCrossRefGoogle Scholar
  34. 34.
    Boffa LC, Morris PL, Carpaneto E et al. Invasion of the CAG triplet repeats by a complementary peptide nucleic acid inhibits transcription of the androgen receptor and TATA-binding protein genes and correlates with refolding of an active nucleosome containing a unique AR gene sequence. J Biol Chem 1996; 271:13228–13233.PubMedCrossRefGoogle Scholar
  35. 35.
    Gorlich D, Mattaj IW. Nucleocytoplasmic transport. Science 1996; 271:1513–1518.PubMedCrossRefGoogle Scholar
  36. 36.
    Branden LJ, Mohamed A, Smith CI. A peptide nucleic acid-nuclear localization signal fusion that mediates nuclear transport of DNA. Nat Biotechnol 1999; 17:784–787.PubMedCrossRefGoogle Scholar
  37. 37.
    Watson J. Origin of concatemeric T7 DNA. Nat Biol 1972; 239:197–201.Google Scholar
  38. 38.
    Counter CM, Avilion AA, LeFeuvre CE et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 1992; 11:1921–1929.PubMedGoogle Scholar
  39. 39.
    Feng J, Funk WD, Wang SS et al. The RNA component of human telomerase. Science 1995, 269:1236–1241.PubMedCrossRefGoogle Scholar
  40. 40.
    Harrington L, Zhou W, McPhail T et al. Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev 1997, 11:3109–3115.PubMedGoogle Scholar
  41. 41.
    Harrington L, McPhail T, Mar V et al. A mammalian telomerase-associated protein. Science 1997, 275:973–977.PubMedCrossRefGoogle Scholar
  42. 42.
    Hahn WC, Counter CM, Lundberg AS et al. Creation of human tumour cells with defined genetic elements. Nature 1999; 400:464–468.PubMedCrossRefGoogle Scholar
  43. 43.
    Raymond E, Sun D, Chen SF et al. Agents that target telomerase and telomeres. Curr Opin Biotech 1996; 7:583–591.PubMedCrossRefGoogle Scholar
  44. 44.
    Glukhov AI, Zimnik OV, Gordeev SA et al. Inhibition of telomerase activity of melanoma cells in vitro by antisense oligonucleotides. Biochem Biophys Res Commun 1998; 248:368–371.PubMedCrossRefGoogle Scholar
  45. 45.
    Pitts AE, Corey DR. Inhibition of human telomerase by 2′-O-methyl-RNA. Proc Natl Acad Sci USA 1998; 95:11549–11554.PubMedCrossRefGoogle Scholar
  46. 46.
    Kondo S, Tanaka Y, Kondo Y et al. Antisense telomerase: Induction of two distinct pathways, apoptosis and differentiation. FASEB J 1998; 12:801–811.PubMedGoogle Scholar
  47. 47.
    Folini M, Colella G, Villa R et al. Inhibition of telomerase activity by a hammerhead ribozyme targeting the RNA component of telomerase in human melanoma cells. J Investig Dermatol 2000; 114:259–267.PubMedCrossRefGoogle Scholar
  48. 48.
    Eckstein F. The hammerhead ribozyme. Biochem Soc Trans 1996; 24:601–604.PubMedGoogle Scholar
  49. 49.
    Scanlon KJ, Kashani-Sabet M. Ribozymes as therapeutic agents: Are we getting closer? J Natl Cancer Inst 1998; 90:558–559.PubMedCrossRefGoogle Scholar
  50. 50.
    Masuda Y, Kobayashi H, Holland JF et al. Reversal of multidrug resistance by a liposome-MDR1 ribozyme complex. Cancer Chemother Pharmacol 1998; 42:9–16.PubMedCrossRefGoogle Scholar
  51. 51.
    Hahn WC, Stewart SA, Brooks MW et al. Inhibition of telomerase limits the growth of human cancer cells. Nature Med 1999, 5:1164–1170.PubMedCrossRefGoogle Scholar

Copyright information

© and Kluwer Academic / Plenum Publishers 2006

Authors and Affiliations

  • Nadia Zaffaroni
    • 1
  • Raffaella Villa
    • 1
  • Marco Folini
    • 1
  1. 1.Dipartimento di Oncologia SperimentaleIstituto Nazionale per lo Studio e la Cura dei TumoriMilanItaly

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