Molecular Biotechnology

, Volume 41, Issue 2, pp 194–199

Strategies Targeting Telomerase Inhibition

Review

Abstract

Telomerase plays a pivotal role in cellular immortality and tumorigenesis. Its activity is normally not detectable in most somatic cells while it is reactivated in the vast majority of cancer cells. Therefore, inhibition of telomerase has been viewed as a promising anticancer approach due to its specificity for cancer cells. Studies so far have shown that telomerase inhibition can inhibit the proliferation of cancer cells or cause apoptosis while it has no effect on most normal cells. Strategies currently being applied to induce telomerase inhibition target virtually all of the major components of the ribonucleoprotein holoenzyme and related cell signal pathways that regulate its activity. These strategies include inhibition of telomerase through targeting at the telomerase reverse transcriptase (TERT) catalytic subunit, the telomerase RNA (TR) component, and associated proteins. Other strategies have been developed to target the proteins associated with telomerase at the telomeric ends of chromosomes such as tankyrase. The specific mechanisms that mediate those inhibition effects include small molecules, antisense RNA, and ribozymes. Although the beneficial evidence of telomerase inhibition is obvious, limitations of strategies remain to be resolved to increase the feasibility of clinical application. This analysis will summarize recent developments of strategies in telomerase inhibition.

Keywords

Telomerase Inhibition Technique Method Telomerase reverse transcriptase (TERT) Telomerase RNA (TR) 

References

  1. 1.
    Ishikawa, F. (1997). Regulation mechanisms of mammalian telomerase. A review. Biochemistry. Biokhimiia, 62, 1332–1337.Google Scholar
  2. 2.
    Weinrich, S., Pruzan, R., Ma, L., Ouellette, M., Tesmer, V., Holt, S., et al. (1997). Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTERT. Nature Genetics, 17, 498–502. doi:10.1038/ng1297-498.CrossRefGoogle Scholar
  3. 3.
    Beattie, T., Zhou, W., Robinson, M., & Harrington, L. (1998). Reconstitution of human telomerase activity in vitro. Current Biology, 8, 177–180. doi:10.1016/S0960-9822(98)70067-3.CrossRefGoogle Scholar
  4. 4.
    Shay, J., & Bacchetti, S. (1997). A survey of telomerase activity in human cancer. European Journal of Cancer, 33, 787–791. doi:10.1016/S0959-8049(97)00062-2.CrossRefGoogle Scholar
  5. 5.
    Ahmed, A., & Tollefsbol, T. (2001). Telomeres and telomerase: Basic science implications for aging. Journal of the American Geriatrics Society, 49, 1105–1109. doi:10.1046/j.1532-5415.2001.49217.x.CrossRefGoogle Scholar
  6. 6.
    Saldanha, S., Andrews, L., & Tollefsbol, T. (2003). Analysis of telomerase activity and detection of its catalytic subunit, hTERT. Analytical Biochemistry, 315, 1–21. doi:10.1016/S0003-2697(02)00663-2.CrossRefGoogle Scholar
  7. 7.
    Hodes, R. (2001). Molecular targeting of cancer: Telomeres as targets. Proceedings of the National Academy of Sciences of the United States of America, 98, 7649–7651. doi:10.1073/pnas.151267698.CrossRefGoogle Scholar
  8. 8.
    Ahmed, A., & Tollefsbol, T. (2003). Telomeres, telomerase, and telomerase inhibition: Clinical implications for cancer. Journal of the American Geriatrics Society, 51, 116–122. doi:10.1034/j.1601-5215.2002.51019.x.CrossRefGoogle Scholar
  9. 9.
    Crooke, S. (1999). Molecular mechanisms of action of antisense drugs. Biochimica et Biophysica Acta, 1489, 31–44.Google Scholar
  10. 10.
    Kraemer, K., Fuessel, S., Schmidt, U., Kotzsch, M., Schwenzer, B., Wirth, M., et al. (2003). Antisense-mediated hTERT inhibition specifically reduces the growth of human bladder cancer cells. Clinical Cancer Research, 9, 3794–3800.Google Scholar
  11. 11.
    Kraemer, K., Fuessel, S., & Meye, A. (2007). Telomerase inhibition by synthetic nucleic acids and chemosensitization in human bladder cancer cell lines. Methods in Molecular Biology (Clifton, N.J.), 405, 9–22. doi:10.1007/978-1-60327-070-0_2.CrossRefGoogle Scholar
  12. 12.
    Agrawal, N., Dasaradhi, P., Mohmmed, A., Malhotra, P., Bhatnagar, R., & Mukherjee, S. (2003). RNA interference: Biology, mechanism, and applications. Microbiology and Molecular Biology Reviews, 67, 657–685. doi:10.1128/MMBR.67.4.657-685.2003.CrossRefGoogle Scholar
  13. 13.
    Lai, S., Andrews, L., & Tollefsbol, T. (2007). hTERT knockdown in human embryonic kidney cells using double-stranded RNA. Methods in Molecular Biology (Clifton, N.J.), 405, 23–29. doi:10.1007/978-1-60327-070-0_3.CrossRefGoogle Scholar
  14. 14.
    Lai, S., Andrews, L., & Tollefsbol, T. (2007). RNA interference using a plasmid construct expressing short-hairpin RNA. Methods in Molecular Biology (Clifton, N.J.), 405, 31–37. doi:10.1007/978-1-60327-070-0_4.CrossRefGoogle Scholar
  15. 15.
    Cunningham, A., Andrews, L., & Tollefsbol, T. (2007). Retrovirus-mediated RNA interference. Targeting hTERT through stable expression of short-hairpin RNA. Methods in Molecular Biology (Clifton, N.J.), 405, 39–46. doi:10.1007/978-1-60327-070-0_5.CrossRefGoogle Scholar
  16. 16.
    Fletcher, T., Cathers, B., Ravikumar, K., Mamiya, B., & Kerwin, S. (2001). Inhibition of human telomerase by 7-deaza-2’-deoxyguanosine nucleoside triphosphate analogs: Potent inhibition by 6-thio-7-deaza-2’-deoxyguanosine 5’-triphosphate. Bioorganic Chemistry, 29, 36–55. doi:10.1006/bioo.2000.1194.CrossRefGoogle Scholar
  17. 17.
    El Daly, H., & Martens, U. (2007). Telomerase inhibition and telomere targeting in hematopoietic cancer cell lines with small non-nucleosidic synthetic compounds (BIBR1532). Methods in Molecular Biology (Clifton, N.J.), 405, 47–60. doi:10.1007/978-1-60327-070-0_6.CrossRefGoogle Scholar
  18. 18.
    Li, H., Katik, I., & Liu, J. (2007). Uses of telomerase peptides in anti-tumor immune therapy. Methods in Molecular Biology (Clifton, N.J.), 405, 61–86. doi:10.1007/978-1-60327-070-0_7.CrossRefGoogle Scholar
  19. 19.
    Huang, Y., Shih, J., & Lin, J. (2007). Establishing cell-based reporter systems for the analysis of hTERT expression. Methods in Molecular Biology (Clifton, N.J.), 405, 87–96. doi:10.1007/978-1-60327-070-0_8.CrossRefGoogle Scholar
  20. 20.
    Kondo, Y., & Kondo, S. (2007). Telomerase RNA inhibition using antisense oligonucleotide against human telomerase RNA linked to a 2’,5’-oligoadenylate. Methods in Molecular Biology (Clifton, N.J.), 405, 97–112. doi:10.1007/978-1-60327-070-0_9.CrossRefGoogle Scholar
  21. 21.
    Li, S., Nosrati, M., & Kashani-Sabet, M. (2007). Knockdown of telomerase RNA using hammerhead ribozymes and RNA interference. Methods in Molecular Biology (Clifton, N.J.), 405, 113–131. doi:10.1007/978-1-60327-070-0_10.CrossRefGoogle Scholar
  22. 22.
    Ohishi, T., Tsuruo, T., & Seimiya, H. (2007). Evaluation of tankyrase inhibition in whole cells. Methods in Molecular Biology (Clifton, N.J.), 405, 133–146. doi:10.1007/978-1-60327-070-0_11.CrossRefGoogle Scholar
  23. 23.
    Xu, D., Li, H., & Liu, J. (2007). Inhibition of telomerase by targeting MAP kinase signaling. Methods in Molecular Biology (Clifton, N.J.), 405, 147–165. doi:10.1007/978-1-60327-070-0_12.CrossRefGoogle Scholar
  24. 24.
    Kleideiter, E., Piotrowska, K., & Klotz, U. (2007). Screening of telomerase inhibitors. Methods in Molecular Biology (Clifton, N.J.), 405, 167–180. doi:10.1007/978-1-60327-070-0_13.CrossRefGoogle Scholar
  25. 25.
    Tauchi, T., Ohyashiki, J., & Ohyashiki, K. (2007). Telomerase inhibition combined with other chemotherapeutic reagents to enhance anti-cancer effect. Methods in Molecular Biology (Clifton, N.J.), 405, 181–189. doi:10.1007/978-1-60327-070-0_14.CrossRefGoogle Scholar
  26. 26.
    Tauchi, T., Shin-Ya, K., Sashida, G., Sumi, M., Nakajima, A., Shimamoto, T., et al. (2003). Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: Involvement of ATM-dependent DNA damage response pathways. Oncogene, 22, 5338–5347. doi:10.1038/sj.onc.1206833.CrossRefGoogle Scholar

Copyright information

© Humana Press 2008

Authors and Affiliations

  • Huaping Chen
    • 1
  • Yuanyuan Li
    • 1
  • Trygve O. Tollefsbol
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of BiologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Center for AgingUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Clinical Nutrition Research CenterUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations