Cancer Letters
Volume 194, Issue 2 , Pages 209-219 , 15 May 2003

Telomerase inhibition as cancer therapy

Received 10 September 2002 ,Revised 29 October 2002 ,Accepted 29 October 2002.

References 

  1. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur. J. Cancer. 1997;33:787–791
  2. Keith WN, Bilsland A, Evans TRJ, Glasspool RM. Telomerase-directed molecular therapeutics. Expert Rev. Mol. Med. 2002 April 22;
  3. Vonderheide RH. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene. 2002;21:674–679
  4. Chang JT, Chen YL, Yang HT, Chen CY, Cheng AJ. Differential regulation of telomerase activity by six telomerase subunits. Eur. J. Biochem. 2002;269:3442–3450
  5. Feng J, Funk WD, Wang SS, Weinrich SL, Avilon AA, Chu CP, et al. The RNA component of human telomerase. Science. 1995;269:1236–1241
  6. Kondo S, Kondo Y, Li G, Silverman RH, Cowell JK. Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA. Oncogene. 1998;16:3323–3330
  7. Glukhov AI, Zimnik OV, Gordeev SA, Severin SE. Inhibition of telomerase activity of melanoma cells in vitro by antisense oligonucleotides. Biochem. Biophys. Res. Commun. 1998;248:368–371
  8. Norton JC, Piatyszek MA, Wright WE, Shay JW, Corey DR. Inhibition of human telomerase activity by peptide nucleic acids. Nat. Biotechnol. 1996;14:615–619
  9. Kanazawa Y, Ohkawa K, Ueda K, Mita E, Takehara T, Sasaki Y, et al. Hammerhead ribozyme-mediated inhibition of telomerase activity in extracts of human hepatocellular carcinoma cells. Biochem. Biophys. Res. Commun. 1996;225:570–576
  10. Muller A, Saretzki G, von Zglinicki T. Telomerase inhibition by induced expression of antisense RNA. Adv. Exp. Med. Biol. 1998;451:23–26
  11. Herbert B, Pitts AE, Baker SI, Hamilton SE, Wright WE, Shay JW, et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl. Acad. Sci. USA. 1999;96:14276–14281
  12. Kondo Y, Kondo S, Tanaka Y, Haqqi T, Barna BP, Cowell JK. Inhibition of telomerase increases the susceptibility of human malignant glioblastoma cells to cisplatin-induced apoptosis. Oncogene. 1998;16:2243–2248
  13. Kondo Y, Koga S, Komata T, Kondo S. Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component. Oncogene. 2000;19:2205–2211
  14. Koga S, Kondo Y, Komata T, Kondo S. Treatment of bladder cancer cells in vitro and in vivo with 2-5A antisense telomerase RNA. Gene Ther. 2001;8:654–658
  15. Yatabe N, Kyo S, Kondo S, Kanaya T, Wang Z, Maida Y, et al. 2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells. Cancer Gene Ther. 2002;9:624–630
  16. Kushner DM, Paranjape JM, Bandyopadhyay B, Cramer H, Leaman DW, Kennedy AW, et al. 2-5A antisense directed against telomerase RNA produces apoptosis in ovarian cancer cells. Gynecol Oncol. 2000;76:183–192
  17. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–795
  18. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Linger J, et al. Telomerase catalytic subunit homologs from fission yeast and human. Science. 1997;277:955–959
  19. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO. Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev. 1999;13:2388–2399
  20. Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, et al. Inhibition of telomerase limits the growth of human cancer cells. Nat. Med. 1999;5:1164–1170
  21. Yokoyama Y, Takahashi Y, Shinohara A, Lian Z, Wan X, Niwa K, et al. Attenuation of telomerase activity by a hammerhead ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cells. Cancer Res. 1998;58:5406–5410
  22. Folini M, Colella G, Villa R, Lualdi S, Daidone MG, Zaffaroni N. Inhibition of telomerase activity by a hammerhead ribozyme targeting the RNA component of telomerase in human melanoma cells. J. Invest. Dermatol. 2000;114:259–267
  23. Yokoyama Y, Takahashi Y, Shinohara A, Wan X, Takahashi S, Niwa K, et al. The 5′-end of hTERT mRNA is a good target for hammerhead ribozyme to suppress telomerase activity. Biochem. Biophys. Res. Commun. 2000;273:316–321
  24. Qu Y, Liu SQ, Peng WZ, Liu BL. Inhibition of telomerase activity by ribozyme targeted to human telomerase transcriptase [in Chinese]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002;34:323–328
  25. Ludwig A, Saretzki G, Holm PS, Tiemann F, Lorenz M, Emrich T, et al. Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase. Cancer Res. 2001;61:3053–3061
  26. Lorenz M, Saretzki G, Sitte N, Metzkow S, von Zglinicki T. BJ fibroblasts display high antioxidant capacity and slow telomere shortening independent of hTERT transfection. Free Radic. Biol. Med. 2001;31:824–831
  27. Saretzki G, Ludwig A, von Zglinicki T, Runnebaum IB. Ribozyme-mediated telomerase inhibition induces immediate cell loss but not telomere shortening in ovarian cancer cells. Cancer Gene Ther. 2001;8:827–834
  28. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. Mammalian telomeres end in a large duplex loop. Cell. 1999;97:503–514
  29. Makarov VL, Hirose Y, Langmore JP. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell. 1997;88:657–666
  30. Sen D, Gilbert W. Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature. 1988;334:364–366
  31. Liu Z, Lee A, Gilbert W. Gene disruption of a G4-DNA-dependent nuclease in yeast leads to cellular senescence and telomere shortening. Proc. Natl. Acad. Sci. USA. 1995;92:6002–6006
  32. Rezler EM, Bearss DJ, Hurley LH. Telomeres and telomerases as drug targets. Curr. Opin. Pharmacol. 2002;2:415–423
  33. Gowan SM, Heald R, Stevens MF, Kelland LR. Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. Mol. Pharmacol. 2001;60:981–988
  34. Gowan SM, Harrison JR, Patterson L, Valenti M, Read MA, Neidle S, et al. A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol. Pharmacol. 2002;61:1154–1162
  35. Blackburn E. The telomere and telomerase: how do they interact?. Mt. Sinai J. Med. 1999;66:292–300
  36. Blackburn EH. Telomere states and cell fates. Nature. 2000;408:53–56
  37. Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106:661–673
  38. de Lange T. Protection of mammalian telomeres. Oncogene. 2002;21:532–540
  39. Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Proc. Natl. Acad. Sci. USA. 2001;98:7982–7987
  40. Cao Y, Li H, Deb S, Liu JP. TERT regulates cell survival independent of telomerase enzymatic activity. Oncogene. 2002;21:3130–3138
  41. Blasco MA. Opinion: Telomerase beyond telomeres. Nat. Rev. Cancer. 2002;2:627–633
  42. Stansel RM, de Lange T, Griffith JD. T-loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang. EMBO J. 2001;20:5532–5540
  43. Zhou XZ, Lu KP. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell. 2001;107:347–359
  44. Ishibashi K, Wakasugi S, Ogawa K, Kato H, Endo S, Yoshimatsu K, et al. Detection of telomerase activity in intestinal lavage solution from colorectal carcinoma patients [in Japanese]. Nippon Rinsho. 1998;56:1209–1213
  45. Zhang RG, Zhang RP, Wang XW, Xie H. Effects of cisplatin on telomerase activity and telomere length in BEL-7404 human hepatoma cells. Cell Res. 2002;12:55–62
  46. Kondo Y, Komata T, Kondo S. Combination therapy of 2-5A antisense against telomerase RNA and cisplatin for malignant gliomas. Int. J. Oncol. 2001;18:1287–1292
  47. Folini M, De Marco C, Orlandi L, Daidone MG, Zaffaroni N. Attenuation of telomerase activity does not increase sensitivity of human melanoma cells to anticancer agents. Eur. J. Cancer. 2000;36:2137–2145
  48. Lee KH, Rudolph KL, Ju YJ, Greenberg RA, Cannizzaro L, Chin L, et al. Telomere dysfunction alters the chemotherapeutic profile of transformed cells. Proc. Natl. Acad. Sci. USA. 2001;98:3381–3386
  49. Yoon HJ, Choi IY, Kang MR, Kim SS, Muller MT, Spitzner JR, et al. DNA topoisomerase II cleavage of telomeres in vitro and in vivo. Biochim. Biophys. Acta. 1998;1395:110–120
  50. Elmore LW, Rehder CW, Di X, McChesney PA, Jackson-Cook CK, Gerwirtz DA, et al. Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. J. Biol. Chem. 2002;35509–35515
  51. von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem. Sci. 2002;27:339–344
  52. Cressey TR, Tilby MJ, Newell DR. Decreased telomerase activity is not a reliable indicator of chemosensitivity in testicular cancer cell lines. Eur. J. Cancer. 2002;38:586–593
  53. Lyu SY, Choi SH, Park WB. Korean mistletoe lectin-induced apoptosis in hepatocarcinoma cells is associated with inhibition of telomerase via mitochondrial controlled pathway independent of p53. Arch. Pharm. Res. 2002;25:93–101
  54. Giridharan P, Somasundaram ST, Perumal K, Vishwakarma RA, Karthikeyan NP, Velmurugan R, et al. Novel substituted methylenedioxy lignan suppresses proliferation of cancer cells by inhibiting telomerase and activation of c-myc and caspases leading to apoptosis. Br. J. Cancer. 2002;87:98–105
  55. Naasani I, Seimiya H, Tsuruo T. Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins. Biochem. Biophys. Res. Commun. 1998;249:391–396
  56. Kim MY, Vankayalapati H, Shin-Ya K, Wierzba K, Hurley LH. Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular G-quadruplex. J. Am. Chem. Soc. 2002;124:2098–2099
  57. Lian Z, Fujimoto J, Yokoyama Y, Niwa K, Tamaya T. Herbal complex suppresses telomerase activity in chemo-endocrine resistant cancer cell lines. Eur. J. Gynaecol. Oncol. 2001;22:347–349
  58. Strahl C, Blackburn EH. Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines. Mol Cell Biol. 1996;16:53–65
  59. Melana SM, Holland JF, Pogo BG. Inhibition of cell growth and telomerase activity of breast cancer cells in vitro by 3′-azido-3′-deoxythymidine. Clin Cancer Res. 1998;4:693–696
  60. Tejera AM, Alonso DF, Gomez DE, Olivero OA. Chronic in vitro exposure to 3′-azido-2′,3′-dideoxythymidine induces senescence and apoptosis and reduces tumorigenicity of metastatic mouse mammary tumor cells. Breast Cancer Res. Treat. 2001;65:93–99
  61. Olivero OA, Poirier MC. Preferential incorporation of 3′-azido-2′,3′-dideoxythymidine into telomeric DNA and Z-DNA-containing regions of Chinese hamster ovary cells. Mol. Carcinog. 1993;8:81–88
  62. Fletcher TM, Cathers BE, Ravikumar KS, Mamiya BM, Kerwin SM. Inhibition of human telomerase by 7-deaza-2′-deoxyguanosine nucleoside triphosphate analogs: potent inhibition by 6-thio-7-deaza-2′-deoxyguanosine 5′-triphosphate. Bioorg. Chem. 2001;29:36–55
  63. Naasani I, Seimiya H, Yamori T, Tsuruo T. FJ5002: a potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis. Cancer Res. 1999;59:4004–4011
  64. Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I, Priepke H, et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 2001;20:6958–6968
  65. Pascolo E, Wenz C, Lingner J, Hauel N, Priepke H, Kauffmann I, et al. Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate. J. Biol. Chem. 2002;277:15566–15572
  66. Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. 1999;13:817–826
  67. Cong YS, Wen J, Bacchetti S. The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum. Mol. Genet. 1999;8:137–142
  68. Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, et al. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 1999;59:551–557
  69. Poole JC, Andrews LG, Tollefsbol TO. Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT). Gene. 2001;269:1–12
  70. Zhao JQ, Hoare SF, McFarlane R, Muir S, Parkinson EK, Black DM, et al. Cloning and characterization of human and mouse telomerase RNA gene promoter sequences. Oncogene. 1998;16:1345–1350
  71. Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M, et al. Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic Acids Res. 2000;28:669–677
  72. Wang Z, Kyo S, Takakura M, Tanaka M, Yatabe N, Maida Y, et al. Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway. Cancer Res. 2000;60:5376–5381
  73. Gunes C, Lichtsteiner S, Vasserot AP, Englert C. Expression of the hTERT gene is regulated at the level of transcriptional initiation and repressed by Mad1. Cancer Res. 2000;60:2116–2121
  74. Oh S, Song YH, Yim J, Kim TK. Identification of Mad as a repressor of the human telomerase (hTERT) gene. Oncogene. 2000;19:1485–1490
  75. Oh S, Song Y, Yim J, Kim TK. The Wilms’ tumor 1 tumor suppressor gene represses transcription of the human telomerase reverse transcriptase gene. J. Biol. Chem. 1999;274:37473–37478
  76. Oh S, Song YH, Kim UJ, Yim J, Kim TK. In vivo and in vitro analyses of Myc for differential promoter activities of the human telomerase (hTERT) gene in normal and tumor cells. Biochem. Biophys. Res. Commun. 1999;263:361–365
  77. Crowe DL, Nguyen DC, Tsang KJ, Kyo S. E2F-1 represses transcription of the human telomerase reverse transcriptase gene. Nucleic Acids Res. 2001;29:2789–2794
  78. Grand CL, Han H, Muñoz RM, Weimann S, Von Hoff DD, Hurley LH, et al. The cationic porphyrin TMPyP4 downregulates c-Myc and hTERT expression and inhibits tumor growth in vivo. Mol. Cancer Ther. 2002;1:565–573
  79. Li H, Lee TH, Avraham H. A novel tricomplex of BRCA1, Nmi, and c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer. J. Biol. Chem. 2002;277:20965–20973
  80. Colgin LM, Wilkinson C, Englezou A, Kilian A, Robinson MO, Reddel RR. The hTERTalpha splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia. 2000;2:426–432
  81. Cerezo A, Kalthoff H, Schuermann M, Schafer B, Boukamp P. Dual regulation of telomerase activity through c-Myc-dependent inhibition and alternative splicing of hTERT. J. Cell Sci. 2002;115:1305–1312
  82. Kyo S, Takakura M, Kanaya T, Zhuo W, Fujimoto K, Nishio Y, et al. Estrogen activates telomerase. Cancer Res. 1999;59:5917–5921
  83. Misiti S, Nanni S, Fontemaggi G, Cong YS, Wen J, Hirte HW, et al. Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells. Mol. Cell. Biol. 2000;20:3764–3771
  84. Pendino F, Flexor M, Delhommeau F, Buet D, Lanotte M, Segal-Bendirdjian E. Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation. Proc. Natl. Acad. Sci. USA. 2001;98:6662–6667
  85. Ding Z, Green AG, Yang X, Chernenko G, Tang SC, Pater A. Retinoic acid inhibits telomerase activity and downregulates expression but does not affect splicing of hTERT: correlation with cell growth rate inhibition in an in vitro cervical carcinogenesis/multidrug-resistance model. Exp. Cell Res. 2002;272:185–191
  86. Cong YS, Bacchetti S. Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells. J. Biol. Chem. 2000;275:35665–35668
  87. Aldous WK, Marean AJ, DeHart MJ, Matej LA, Moore KH. Effects of tamoxifen on telomerase activity in breast carcinoma cell lines. Cancer. 1999;85:1523–1529
  88. Wang Z, Kyo S, Maida Y, Takakura M, Tanaka M, Yatabe N, et al. Tamoxifen regulates human telomerase reverse transcriptase (hTERT) gene expression differently in breast and endometrial cancer cells. Oncogene. 2002;21:3517–3524
  89. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–460
  90. von Zglinicki T, Saretzki G, Docke W, Lotze C. Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?. Exp. Cell Res. 1995;220:186–193
  91. Petersen S, Saretzki G, von Zglinicki T. Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp. Cell Res. 1998;239:152–160
  92. Plumb JA, Bilsland A, Kakani R, Zhao J, Glasspool RM, Knox RJ, et al. Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954. Oncogene. 2001;20:7797–7803
  93. Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth JA. Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers. Cancer Res. 2000;60:5359–5364
  94. Mukai S, Kondo Y, Koga S, Komata T, Barna BP, Kondo S. 2-5A antisense telomerase RNA therapy for intracranial malignant gliomas. Cancer Res. 2000;60:4461–4467
  95. Fu W, Begley JG, Killen MW, Mattson MP. Anti-apoptotic role of telomerase in pheochromocytoma cells. J. Biol. Chem. 1999;274:7264–7271
  96. Zhu H, Fu W, Mattson MP. The catalytic subunit of telomerase protects neurons against amyloid beta-peptide-induced apoptosis. J. Neurochem. 2000;75:117–124
  97. Lu C, Fu W, Mattson MP. Telomerase protects developing neurons against DNA damage-induced cell death. Brain Res. Dev. Brain Res. 2001;131:167–171
  98. Mattson MP, Fu W, Zhang P. Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist's perspective. Mech. Ageing Dev. 2001;122:659–671
  99. Cao Y, Li H, Mu FT, Ebisui O, Funder JW, Liu JP. Telomerase activation causes vascular smooth muscle cell proliferation in genetic hypertension. FASEB J. 2002;16:96–98
  100. Oh H, Schneider MD. The emerging role of telomerase in cardiac muscle cell growth and survival. J. Mol. Cell. Cardiol. 2002;34:717–724
  101. Page TJ, Mata JE, Bridge JA, Siebler JC, Neff JR, Iversen PL. The cytotoxic effects of single-stranded telomere mimics on OMA-BL1 cells. Exp. Cell Res. 1999;252:41–49
  102. Saretzki G, Sitte N, Merkel U, Wurm RE, von Zglinicki T. Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments. Oncogene. 1999;18:5148–5158
  103. Holt SE, Glinsky VV, Ivanova AB, Glinsky GV. Resistance to apoptosis in human cells conferred by telomerase function and telomere stability. Mol. Carcinog. 1999;25:241–248

PII: S0304-3835(02)00708-5

doi: 10.1016/S0304-3835(02)00708-5

Cancer Letters
Volume 194, Issue 2 , Pages 209-219 , 15 May 2003

Article Tools