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.
Similar content being viewed by others
References
Ishikawa, F. (1997). Regulation mechanisms of mammalian telomerase. A review. Biochemistry. Biokhimiia, 62, 1332–1337.
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.
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.
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.
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.
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.
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.
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.
Crooke, S. (1999). Molecular mechanisms of action of antisense drugs. Biochimica et Biophysica Acta, 1489, 31–44.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgments
We apologize to those scientists whose work has not been cited in this article due to limited space. This work was supported by grants from the National Cancer Institute (R01 CA129415) and the Susan G. Komen for the Cure.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, H., Li, Y. & Tollefsbol, T.O. Strategies Targeting Telomerase Inhibition. Mol Biotechnol 41, 194–199 (2009). https://doi.org/10.1007/s12033-008-9117-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12033-008-9117-9