Potential Telomere-Related Pharmacological Targets

Joseph       Berei; Adam       Eckburg; Edward       Miliavski; Austin    D.    Anderson; Rachel    J.    Miller; Joshua       Dein; Allison    M.    Giuffre; Diana       Tang; Shreya       Deb; Kavya    Sri    Racherla; Meet       Patel; Monica    Saravana    Vela; Neelu       Puri
doi:10.2174/1568026620666200109114339
Abstract

Telomeres function as protective caps at the terminal portion of chromosomes, containing non-coding nucleotide sequence repeats. As part of their protective function, telomeres preserve genomic integrity and minimize chromosomal exposure, thus limiting DNA damage responses. With continued mitotic divisions in normal cells, telomeres progressively shorten until they reach a threshold at a point where they activate senescence or cell death pathways. However, the presence of the enzyme telomerase can provide functional immortality to the cells that have reached or progressed past senescence. In senescent cells that amass several oncogenic mutations, cancer formation can occur due to genomic instability and the induction of telomerase activity. Telomerase has been found to be expressed in over 85% of human tumors and is labeled as a near-universal marker for cancer. Due to this feature being present in a majority of tumors but absent in most somatic cells, telomerase and telomeres have become promising targets for the development of new and effective anticancer therapeutics. In this review, we evaluate novel anticancer targets in development which aim to alter telomerase or telomere function. Additionally, we analyze the progress that has been made, including preclinical studies and clinical trials, with therapeutics directed at telomere-related targets. Furthermore, we review the potential telomere-related therapeutics that are used in combination therapy with more traditional cancer treatments. Throughout the review, topics related to medicinal chemistry are discussed, including drug bioavailability and delivery, chemical structure-activity relationships of select therapies, and the development of a unique telomere assay to analyze compounds affecting telomere elongation.
Keywords: Telomere, Telomerase, Cancer, Shelterin, hTERT, ATM, G-Quadruplex, T-oligo.
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[1] 
Blackburn, E.H. Telomerase and Cancer: Kirk A. Landon--AACR prize for basic cancer research lecture. Mol. Cancer Res.,  2005, 3(9), 477-482.
[http://dx.doi.org/10.1158/1541-7786.MCR-05-0147] [PMID: 16179494] 
[2] 
Blackburn, E.H.; Greider, C.W.; Szostak, J.W. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat. Med.,  2006, 12(10), 1133-1138.
[http://dx.doi.org/10.1038/nm1006-1133] [PMID: 17024208] 
[3] 
Crees, Z.; Girard, J.; Rios, Z.; Botting, G.M.; Harrington, K.; Shearrow, C.; Wojdyla, L.; Stone, A.L.; Uppada, S.B.; Devito, J.T.; Puri, N. Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy. Curr. Pharm. Des.,  2014, 20(41), 6422-6437.
[http://dx.doi.org/10.2174/1381612820666140630100702] [PMID: 24975605] 
[4] 
Harley, C.B. Telomerase and cancer therapeutics. Nat. Rev. Cancer,  2008, 8(3), 167-179.
[http://dx.doi.org/10.1038/nrc2275] [PMID: 18256617] 
[5] 
Tian, X.; Chen, B.; Liu, X. Telomere and telomerase as targets for cancer therapy. Appl. Biochem. Biotechnol.,  2010, 160(5), 1460-1472.
[http://dx.doi.org/10.1007/s12010-009-8633-9] [PMID: 19412578] 
[6] 
Ruden, M.; Puri, N. Novel anticancer therapeutics targeting telomerase. Cancer Treat. Rev.,  2013, 39(5), 444-456.
[http://dx.doi.org/10.1016/j.ctrv.2012.06.007] [PMID: 22841437] 
[7] 
de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev.,  2005, 19(18), 2100-2110.
[http://dx.doi.org/10.1101/gad.1346005] [PMID: 16166375] 
[8] 
Palm, W.; de Lange, T. How shelterin protects mammalian telomeres. Annu. Rev. Genet.,  2008, 42, 301-334.
[http://dx.doi.org/10.1146/annurev.genet.41.110306.130350] [PMID: 18680434] 
[9] 
Greider, C.W.; Blackburn, E.H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell,  1985, 43(2 Pt 1), 405-413.
[http://dx.doi.org/10.1016/0092-8674(85)90170-9] [PMID: 3907856] 
[10] 
Artandi, S.E.; DePinho, R.A. Telomeres and telomerase in cancer. Carcinogenesis,  2010, 31(1), 9-18.
[http://dx.doi.org/10.1093/carcin/bgp268] [PMID: 19887512] 
[11] 
Blackburn, E.H. Telomerases. Annu. Rev. Biochem.,  1992, 61, 113-129.
[http://dx.doi.org/10.1146/annurev.bi.61.070192.000553] [PMID: 1497307] 
[12] 
Jiang, J.; Chan, H.; Cash, D.D.; Miracco, E.J.; Ogorzalek Loo, R.R.; Upton, H.E.; Cascio, D.; O’Brien Johnson, R.; Collins, K.; Loo, J.A.; Zhou, Z.H.; Feigon, J. Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions. Science,  2015, 350(6260), aab4070
[http://dx.doi.org/10.1126/science.aab4070] [PMID: 26472759] 
[13] 
Wu, R.A.; Dagdas, Y.S.; Yilmaz, S.T.; Yildiz, A.; Collins, K. Single-molecule imaging of telomerase reverse transcriptase in human telomerase holoenzyme and minimal RNP complexes. eLife,  2015, 4, 4.
[http://dx.doi.org/10.7554/eLife.08363] [PMID: 26457608] 
[14] 
Kim, N.W.; Piatyszek, M.A.; Prowse, K.R.; Harley, C.B.; West, M.D.; Ho, P.L.; Coviello, G.M.; Wright, W.E.; Weinrich, S.L.; Shay, J.W. Specific association of human telomerase activity with immortal cells and cancer. Science,  1994, 266(5193), 2011-2015.
[http://dx.doi.org/10.1126/science.7605428] [PMID: 7605428] 
[15] 
Shay, J.W.; Bacchetti, S. A survey of telomerase activity in human cancer. Eur. J. Cancer,  1997, 33(5), 787-791.
[http://dx.doi.org/10.1016/S0959-8049(97)00062-2] [PMID: 9282118] 
[16] 
O’Sullivan, R.J.; Karlseder, J. Telomeres: protecting chromosomes against genome instability. Nat. Rev. Mol. Cell Biol.,  2010, 11(3), 171-181.
[http://dx.doi.org/10.1038/nrm2848] [PMID: 20125188] 
[17] 
Hayflick, L.; Moorhead, P.S. The serial cultivation of human diploid cell strains. Exp. Cell Res.,  1961, 25, 585-621.
[http://dx.doi.org/10.1016/0014-4827(61)90192-6] [PMID: 13905658] 
[18] 
Rankin, A.M.; Faller, D.V.; Spanjaard, R.A. Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity. Anticancer Drugs,  2008, 19(4), 329-338.
[http://dx.doi.org/10.1097/CAD.0b013e3282f5d4c2] [PMID: 18454043] 
[19] 
Wright, W.E.; Shay, J.W. Historical claims and current interpretations of replicative aging. Nat. Biotechnol.,  2002, 20(7), 682-688.
[http://dx.doi.org/10.1038/nbt0702-682] [PMID: 12089552] 
[20] 
Shay, J.W.; Wright, W.E. Quantitation of the frequency of immortalization of normal human diploid fibroblasts by SV40 large T-antigen. Exp. Cell Res.,  1989, 184(1), 109-118.
[http://dx.doi.org/10.1016/0014-4827(89)90369-8] [PMID: 2551703] 
[21] 
Shay, J.W. Role of Telomeres and Telomerase in Aging and Cancer. Cancer Discov.,  2016, 6(6), 584-593.
[http://dx.doi.org/10.1158/2159-8290.CD-16-0062] [PMID: 27029895] 
[22] 
Bisoffi, M.; Heaphy, C.M.; Griffith, J.K. Telomeres: prognostic markers for solid tumors. Int. J. Cancer,  2006, 119(10), 2255-2260.
[http://dx.doi.org/10.1002/ijc.22120] [PMID: 16858685] 
[23] 
Dikmen, Z.G.; Wright, W.E.; Shay, J.W.; Gryaznov, S.M. Telomerase targeted oligonucleotide thio-phosphoramidates in T24-luc bladder cancer cells. J. Cell. Biochem.,  2008, 104(2), 444-452.
[http://dx.doi.org/10.1002/jcb.21635] [PMID: 18044713] 
[24] 
de Lange, T. Protection of mammalian telomeres. Oncogene,  2002, 21(4), 532-540.
[http://dx.doi.org/10.1038/sj.onc.1205080] [PMID: 11850778] 
[25] 
Jafri, M.A.; Ansari, S.A.; Alqahtani, M.H.; Shay, J.W. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med.,  2016, 8(1), 69.
[http://dx.doi.org/10.1186/s13073-016-0324-x] [PMID: 27323951] 
[26] 
Ivancich, M.; Schrank, Z.; Wojdyla, L.; Leviskas, B.; Kuckovic, A.; Sanjali, A.; Puri, N. Treating cancer by targeting telomeres and telomerase. Antioxidants,  2017, 6(1), E15
[http://dx.doi.org/10.3390/antiox6010015] [PMID: 28218725] 
[27] 
Ribes-Zamora, A.; Indiviglio, S.M.; Mihalek, I.; Williams, C.L.; Bertuch, A.A. TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres. Cell Rep.,  2013, 5(1), 194-206.
[http://dx.doi.org/10.1016/j.celrep.2013.08.040] [PMID: 24095731] 
[28] 
Griffith, J.D.; Comeau, L.; Rosenfield, S.; Stansel, R.M.; Bianchi, A.; Moss, H.; de Lange, T. Mammalian telomeres end in a large duplex loop. Cell,  1999, 97(4), 503-514.
[http://dx.doi.org/10.1016/S0092-8674(00)80760-6] [PMID: 10338214] 
[29] 
Dunham, M.A.; Neumann, A.A.; Fasching, C.L.; Reddel, R.R. Telomere maintenance by recombination in human cells. Nat. Genet.,  2000, 26(4), 447-450.
[http://dx.doi.org/10.1038/82586] [PMID: 11101843] 
[30] 
Luke-Glaser, S.; Poschke, H.; Luke, B. Getting in (and out of) the loop: regulating higher order telomere structures. Front. Oncol.,  2012, 2, 180.
[http://dx.doi.org/10.3389/fonc.2012.00180] [PMID: 23226680] 
[31] 
Lee, S.S.; Bohrson, C.; Pike, A.M.; Wheelan, S.J.; Greider, C.W. ATM kinase is required for telomere elongation in mouse and human Cells. Cell Rep.,  2015, 13(8), 1623-1632.
[http://dx.doi.org/10.1016/j.celrep.2015.10.035] [PMID: 26586427] 
[32] 
Li, M.; Fu, W.; Wo, L.; Shu, X.; Liu, F.; Li, C. miR-128 and its target genes in tumorigenesis and metastasis. Exp. Cell Res.,  2013, 319(20), 3059-3064.
[http://dx.doi.org/10.1016/j.yexcr.2013.07.031] [PMID: 23958464] 
[33] 
Sarin, K.Y.; Cheung, P.; Gilison, D.; Lee, E.; Tennen, R.I.; Wang, E.; Artandi, M.K.; Oro, A.E.; Artandi, S.E. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature,  2005, 436(7053), 1048-1052.
[http://dx.doi.org/10.1038/nature03836] [PMID: 16107853] 
[34] 
Lund, E.; Güttinger, S.; Calado, A.; Dahlberg, J.E.; Kutay, U. Nuclear export of microRNA precursors. Science,  2004, 303(5654), 95-98.
[http://dx.doi.org/10.1126/science.1090599] [PMID: 14631048] 
[35] 
Esquela-Kerscher, A.; Slack, F.J. Oncomirs - microRNAs with a role in cancer. Nat. Rev. Cancer,  2006, 6(4), 259-269.
[http://dx.doi.org/10.1038/nrc1840] [PMID: 16557279] 
[36] 
Schrank, Z.; Khan, N.; Osude, C.; Singh, S.; Miller, R.J.; Merrick, C.; Mabel, A.; Kuckovic, A.; Puri, N. Oligonucleotides targeting telomeres and telomerase in cancer. Molecules,  2018, 23(9), E2267
[http://dx.doi.org/10.3390/molecules23092267] [PMID: 30189661] 
[37] 
Guzman, H.; Sanders, K.; Idica, A.; Bochnakian, A.; Jury, D.; Daugaard, I.; Zisoulis, D.G.; Pedersen, I.M. miR-128 inhibits telomerase activity by targeting TERT mRNA. Oncotarget,  2018, 9(17), 13244-13253.
[http://dx.doi.org/10.18632/oncotarget.24284] [PMID: 29568354] 
[38] 
Zhou, N.; Fei, D.; Zong, S.; Zhang, M.; Yue, Y. MicroRNA-138 inhibits proliferation, migration and invasion through targeting hTERT in cervical cancer. Oncol. Lett.,  2016, 12(5), 3633-3639.
[http://dx.doi.org/10.3892/ol.2016.5038] [PMID: 27900047] 
[39] 
Chakrabarti, M.; Banik, N.L.; Ray, S.K. miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo. Exp. Cell Res.,  2013, 319(10), 1575-1585.
[http://dx.doi.org/10.1016/j.yexcr.2013.02.025] [PMID: 23562653] 
[40] 
Song, G.; Wang, R.; Guo, J.; Liu, X.; Wang, F.; Qi, Y.; Wan, H.; Liu, M.; Li, X.; Tang, H. miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively. Sci. Rep.,  2015, 5, 15793.
[http://dx.doi.org/10.1038/srep15793] [PMID: 26507454] 
[41] 
Mitomo, S.; Maesawa, C.; Ogasawara, S.; Iwaya, T.; Shibazaki, M.; Yashima-Abo, A.; Kotani, K.; Oikawa, H.; Sakurai, E.; Izutsu, N.; Kato, K.; Komatsu, H.; Ikeda, K.; Wakabayashi, G.; Masuda, T. Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines. Cancer Sci.,  2008, 99(2), 280-286.
[http://dx.doi.org/10.1111/j.1349-7006.2007.00666.x] [PMID: 18201269] 
[42] 
Li, J.; Lei, H.; Xu, Y.; Tao, Z.Z. miR-512-5p suppresses tumor growth by targeting hTERT in telomerase positive head and neck squamous cell carcinoma in vitro and in vivo. PLoS One,  2015, 10(8), e0135265
[http://dx.doi.org/10.1371/journal.pone.0135265] [PMID: 26258591] 
[43] 
Abdulkareem, I.H.; Blair, M. Phosphatase and tensin homologue deleted on chromosome 10. Niger. Med. J.,  2013, 54(2), 79-86.
[http://dx.doi.org/10.4103/0300-1652.110033] [PMID: 23798791] 
[44] 
Zhu, H.Y.; Li, C.; Bai, W.D.; Su, L.L.; Liu, J.Q.; Li, Y.; Shi, J.H.; Cai, W.X.; Bai, X.Z.; Jia, Y.H.; Zhao, B.; Wu, X.; Li, J.; Hu, D.H. MicroRNA-21 regulates hTERT via PTEN in hypertrophic scar fibroblasts. PLoS One,  2014, 9(5), e97114
[http://dx.doi.org/10.1371/journal.pone.0097114] [PMID: 24817011] 
[45] 
Shen, L.; Chen, X.D.; Zhang, Y.H. MicroRNA-128 promotes proliferation in osteosarcoma cells by downregulating PTEN. Tumour Biol.,  2014, 35(3), 2069-2074.
[http://dx.doi.org/10.1007/s13277-013-1274-1] [PMID: 24132591] 
[46] 
Muñoz, P.; Blanco, R.; de Carcer, G.; Schoeftner, S.; Benetti, R.; Flores, J.M.; Malumbres, M.; Blasco, M.A. TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis. Mol. Cell. Biol.,  2009, 29(6), 1608-1625.
[http://dx.doi.org/10.1128/MCB.01339-08] [PMID: 19124610] 
[47] 
Ancelin, K.; Brunori, M.; Bauwens, S.; Koering, C.E.; Brun, C.; Ricoul, M.; Pommier, J.P.; Sabatier, L.; Gilson, E. Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol. Cell. Biol.,  2002, 22(10), 3474-3487.
[http://dx.doi.org/10.1128/MCB.22.10.3474-3487.2002] [PMID: 11971978] 
[48] 
Smogorzewska, A.; van Steensel, B.; Bianchi, A.; Oelmann, S.; Schaefer, M.R.; Schnapp, G.; de Lange, T. Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol.,  2000, 20(5), 1659-1668.
[http://dx.doi.org/10.1128/MCB.20.5.1659-1668.2000] [PMID: 10669743] 
[49] 
Dinami, R.; Ercolani, C.; Petti, E.; Piazza, S.; Ciani, Y.; Sestito, R.; Sacconi, A.; Biagioni, F.; le Sage, C.; Agami, R.; Benetti, R.; Mottolese, M.; Schneider, C.; Blandino, G.; Schoeftner, S. miR-155 drives telomere fragility in human breast cancer by targeting TRF1. Cancer Res.,  2014, 74(15), 4145-4156.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2038] [PMID: 24876105] 
[50] 
Melnik, B.C. MiR-21: an environmental driver of malignant melanoma? J. Transl. Med.,  2015, 13, 202.
[http://dx.doi.org/10.1186/s12967-015-0570-5] [PMID: 26116372] 
[51] 
Yang, Y.; Yang, J.J.; Tao, H.; Jin, W.S. MicroRNA-21 controls hTERT via PTEN in human colorectal cancer cell proliferation. J. Physiol. Biochem.,  2015, 71(1), 59-68.
[http://dx.doi.org/10.1007/s13105-015-0380-5] [PMID: 25603978] 
[52] 
Ohira, T.; Naohiro, S.; Nakayama, Y.; Osaki, M.; Okada, F.; Oshimura, M.; Kugoh, H. miR-19b regulates hTERT mRNA expression through targeting PITX1 mRNA in melanoma cells. Sci. Rep.,  2015, 5, 8201.
[http://dx.doi.org/10.1038/srep08201] [PMID: 25643913] 
[53] 
Sontheimer, E.J.; Carthew, R.W. Molecular biology. Argonaute journeys into the heart of RISC. Science,  2004, 305(5689), 1409-1410.
[http://dx.doi.org/10.1126/science.1103076] [PMID: 15353786] 
[54] 
Gandhi, N.S.; Tekade, R.K.; Chougule, M.B. Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances. J. Control. Release,  2014, 194, 238-256.
[http://dx.doi.org/10.1016/j.jconrel.2014.09.001] [PMID: 25204288] 
[55] 
Nguyen, D.D.; Chang, S. Development of novel therapeutic agents by inhibition of oncogenic microRNAs. Int. J. Mol. Sci.,  2017, 19(1), E65
[http://dx.doi.org/10.3390/ijms19010065] [PMID: 29280958] 
[56] 
Zhuang, C.L.; Fu, X.; Liu, L.; Liu, Y.C.; Huang, W.R.; Cai, Z.M. Synthetic miRNA sponges driven by mutant hTERT promoter selectively inhibit the progression of bladder cancer. Tumour Biol.,  2015, 36(7), 5157-5163.
[http://dx.doi.org/10.1007/s13277-015-3169-9] [PMID: 25775949] 
[57] 
Vonderheide, R.H.; Hahn, W.C.; Schultze, J.L.; Nadler, L.M. The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity,  1999, 10(6), 673-679.
[http://dx.doi.org/10.1016/S1074-7613(00)80066-7] [PMID: 10403642] 
[58] 
Lev, A.; Denkberg, G.; Cohen, C.J.; Tzukerman, M.; Skorecki, K.L.; Chames, P.; Hoogenboom, H.R.; Reiter, Y. Isolation and characterization of human recombinant antibodies endowed with the antigen-specific, major histocompatibility complex-restricted specificity of T cells directed toward the widely expressed tumor T-cell epitopes of the telomerase catalytic subunit. Cancer Res.,  2002, 62(11), 3184-3194.
[PMID: 12036932] 
[59] 
Vonderheide, R.H. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene,  2002, 21(4), 674-679.
[http://dx.doi.org/10.1038/sj.onc.1205074] [PMID: 11850795] 
[60] 
Vonderheide, R.H. Prospects and challenges of building a cancer vaccine targeting telomerase. Biochimie,  2008, 90(1), 173-180.
[http://dx.doi.org/10.1016/j.biochi.2007.07.005] [PMID: 17716803] 
[61] 
Mizukoshi, E.; Kaneko, S. Telomerase-targeted cancer immunotherapy. Int. J. Mol. Sci.,  2019, 20(8), E1823
[http://dx.doi.org/10.3390/ijms20081823] [PMID: 31013796] 
[62] 
Brunsvig, P.F.; Aamdal, S.; Gjertsen, M.K.; Kvalheim, G.; Markowski-Grimsrud, C.J.; Sve, I.; Dyrhaug, M.; Trachsel, S.; Møller, M.; Eriksen, J.A.; Gaudernack, G. Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol. Immunother.,  2006, 55(12), 1553-1564.
[http://dx.doi.org/10.1007/s00262-006-0145-7] [PMID: 16491401] 
[63] 
Greten, T.F.; Forner, A.; Korangy, F.; N’Kontchou, G.; Barget, N.; Ayuso, C.; Ormandy, L.A.; Manns, M.P.; Beaugrand, M.; Bruix, J. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer,  2010, 10, 209.
[http://dx.doi.org/10.1186/1471-2407-10-209] [PMID: 20478057] 
[64] 
Kyte, J.A.; Gaudernack, G.; Dueland, S.; Trachsel, S.; Julsrud, L.; Aamdal, S. Telomerase peptide vaccination combined with temozolomide: a clinical trial in stage IV melanoma patients. Clin. Cancer Res.,  2011, 17(13), 4568-4580.
[65] 
Inderberg-Suso, E.M.; Trachsel, S.; Lislerud, K.; Rasmussen, A.M.; Gaudernack, G. Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. OncoImmunology,  2012, 1(5), 670-686.
[http://dx.doi.org/10.4161/onci.20426] [PMID: 22934259] 
[66] 
Staff, C.; Mozaffari, F.; Frödin, J.E.; Mellstedt, H.; Liljefors, M. Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients. Int. J. Oncol.,  2014, 45(3), 1293-1303.
[http://dx.doi.org/10.3892/ijo.2014.2496] [PMID: 24919654] 
[67] 
Middleton, G.; Silcocks, P.; Cox, T.; Valle, J.; Wadsley, J.; Propper, D.; Coxon, F.; Ross, P.; Madhusudan, S.; Roques, T.; Cunningham, D.; Falk, S.; Wadd, N.; Harrison, M.; Corrie, P.; Iveson, T.; Robinson, A.; McAdam, K.; Eatock, M.; Evans, J.; Archer, C.; Hickish, T.; Garcia-Alonso, A.; Nicolson, M.; Steward, W.; Anthoney, A.; Greenhalf, W.; Shaw, V.; Costello, E.; Naisbitt, D.; Rawcliffe, C.; Nanson, G.; Neoptolemos, J. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol.,  2014, 15(8), 829-840.
[http://dx.doi.org/10.1016/S1470-2045(14)70236-0] [PMID: 24954781] 
[68] 
Hunger, R.E.; Kernland Lang, K.; Markowski, C.J.; Trachsel, S.; Møller, M.; Eriksen, J.A.; Rasmussen, A.M.; Braathen, L.R.; Gaudernack, G. Vaccination of patients with cutaneous melanoma with telomerase-specific peptides. Cancer Immunol. Immunother.,  2011, 60(11), 1553-1564.
[http://dx.doi.org/10.1007/s00262-011-1061-z] [PMID: 21681371] 
[69] 
Middleton, G.; Greenhalf, W.; Costello, E.; Shaw, V.; Cox, T.; Ghaneh, P.; Palmer, D.H.; Neoptolemos, J.P. Immunobiological effects of gemcitabine and capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma. Br. J. Cancer,  2016, 114(5), 510-518.
[http://dx.doi.org/10.1038/bjc.2015.468] [PMID: 26931369] 
[70] 
Fenoglio, D.; Traverso, P.; Parodi, A.; Tomasello, L.; Negrini, S.; Kalli, F.; Battaglia, F.; Ferrera, F.; Sciallero, S.; Murdaca, G.; Setti, M.; Sobrero, A.; Boccardo, F.; Cittadini, G.; Puppo, F.; Criscuolo, D.; Carmignani, G.; Indiveri, F.; Filaci, G. A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer. Cancer Immunol. Immunother.,  2013, 62(6), 1041-1052.
[http://dx.doi.org/10.1007/s00262-013-1415-9] [PMID: 23591981] 
[71] 
Fenoglio, D.; Parodi, A.; Lavieri, R.; Kalli, F.; Ferrera, F.; Tagliamacco, A.; Guastalla, A.; Lamperti, M.G.; Giacomini, M.; Filaci, G. Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one. Hum. Vaccin. Immunother.,  2015, 11(4), 838-850.
[http://dx.doi.org/10.1080/21645515.2015.1012032] [PMID: 25714118] 
[72] 
Lilleby, W.; Gaudernack, G.; Brunsvig, P.F.; Vlatkovic, L.; Schulz, M.; Mills, K.; Hole, K.H.; Inderberg, E.M. Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer. Cancer Immunol. Immunother.,  2017, 66(7), 891-901.
[http://dx.doi.org/10.1007/s00262-017-1994-y] [PMID: 28391357] 
[73] 
Menez-Jamet, J.; Gallou, C.; Rougeot, A.; Kosmatopoulos, K. Optimized tumor cryptic peptides: the basis for universal neo-antigen-like tumor vaccines. Ann. Transl. Med.,  2016, 4(14), 266.
[http://dx.doi.org/10.21037/atm.2016.05.15] [PMID: 27563653] 
[74] 
Kotsakis, A.; Papadimitraki, E.; Vetsika, E.K.; Aggouraki, D.; Dermitzaki, E.K.; Hatzidaki, D.; Kentepozidis, N.; Mavroudis, D.; Georgoulias, V. A phase II trial evaluating the clinical and immunologic response of HLA-A2(+) non-small cell lung cancer patients vaccinated with an hTERT cryptic peptide. Lung Cancer,  2014, 86(1), 59-66.
[http://dx.doi.org/10.1016/j.lungcan.2014.07.018] [PMID: 25130084] 
[75] 
Kantoff, P.W.; Higano, C.S.; Shore, N.D.; Berger, E.R.; Small, E.J.; Penson, D.F.; Redfern, C.H.; Ferrari, A.C.; Dreicer, R.; Sims, R.B.; Xu, Y.; Frohlich, M.W.; Schellhammer, P.F.; Investigators, I.S. IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med.,  2010, 363(5), 411-422.
[http://dx.doi.org/10.1056/NEJMoa1001294] [PMID: 20818862] 
[76] 
Ouellette, M.M.; Wright, W.E.; Shay, J.W. Targeting telomerase-expressing cancer cells. J. Cell. Mol. Med.,  2011, 15(7), 1433-1442.
[http://dx.doi.org/10.1111/j.1582-4934.2011.01279.x] [PMID: 21332640] 
[77] 
Brower, V. Telomerase-based therapies emerging slowly. J. Natl. Cancer Inst.,  2010, 102(8), 520-521.
[http://dx.doi.org/10.1093/jnci/djq145] [PMID: 20388877] 
[78] 
Vonderheide, R.H.; Domchek, S.M.; Schultze, J.L.; George, D.J.; Hoar, K.M.; Chen, D.Y.; Stephans, K.F.; Masutomi, K.; Loda, M.; Xia, Z.; Anderson, K.S.; Hahn, W.C.; Nadler, L.M. Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes. Clin. Cancer Res.,  2004, 10(3), 828-839.
[79] 
Su, Z.; Dannull, J.; Yang, B.K.; Dahm, P.; Coleman, D.; Yancey, D.; Sichi, S.; Niedzwiecki, D.; Boczkowski, D.; Gilboa, E.; Vieweg, J. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J. Immunol.,  2005, 174(6), 3798-3807.
[http://dx.doi.org/10.4049/jimmunol.174.6.3798] [PMID: 15749921] 
[80] 
Aloysius, M.M.; Mc Kechnie, A.J.; Robins, R.A.; Verma, C.; Eremin, J.M.; Farzaneh, F.; Habib, N.A.; Bhalla, J.; Hardwick, N.R.; Satthaporn, S.; Sreenivasan, T.; El-Sheemy, M.; Eremin, O. Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs. J. Transl. Med.,  2009, 7, 18.
[http://dx.doi.org/10.1186/1479-5876-7-18] [PMID: 19298672] 
[81] 
Khoury, H.J.; Collins, R.H., Jr; Blum, W.; Stiff, P.S.; Elias, L.; Lebkowski, J.S.; Reddy, A.; Nishimoto, K.P.; Sen, D.; Wirth, E.D., III; Case, C.C.; DiPersio, J.F. Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia. Cancer,  2017, 123(16), 3061-3072.
[http://dx.doi.org/10.1002/cncr.30696] [PMID: 28411378] 
[82] 
Salazar-Onfray, F.; Pereda, C.; Reyes, D.; López, M.N. TAPCells, the Chilean dendritic cell vaccine against melanoma and prostate cancer. Biol. Res.,  2013, 46(4), 431-440.
[http://dx.doi.org/10.4067/S0716-97602013000400014] [PMID: 24510145] 
[83] 
Mehrotra, S.; Britten, C.D.; Chin, S.; Garrett-Mayer, E.; Cloud, C.A.; Li, M.; Scurti, G.; Salem, M.L.; Nelson, M.H.; Thomas, M.B.; Paulos, C.M.; Salazar, A.M.; Nishimura, M.I.; Rubinstein, M.P.; Li, Z.; Cole, D.J. Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer. J. Hematol. Oncol.,  2017, 10(1), 82.
[http://dx.doi.org/10.1186/s13045-017-0459-2] [PMID: 28388966] 
[84] 
Smithers, G.W. Reference Module in Food Science; Elsevier: Amsterdam, 2015. 
[85] 
Gupta, K.; Kumar, A.; Tomer, V.; Kumar, V.; Saini, M. Potential of Colocasia leaves in human nutrition: Review on nutritional and phytochemical properties. J. Food Biochem.,  2019, 43(7), e12878
[http://dx.doi.org/10.1111/jfbc.12878] [PMID: 31353694] 
[86] 
Chakraborty, S.; Ghosh, U.; Bhattacharyya, N.P.; Bhattacharya, R.K.; Roy, M. Inhibition of telomerase activity and induction of apoptosis by curcumin in K-562 cells. Mutat. Res.,  2006, 596(1-2), 81-90.
[http://dx.doi.org/10.1016/j.mrfmmm.2005.12.007] [PMID: 16445949] 
[87] 
Sprouse, A.A.; Steding, C.E.; Herbert, B.S. Pharmaceutical regulation of telomerase and its clinical potential. J. Cell. Mol. Med.,  2012, 16(1), 1-7.
[http://dx.doi.org/10.1111/j.1582-4934.2011.01460.x] [PMID: 21973217] 
[88] 
Ganesan, K.; Xu, B. Telomerase inhibitors from natural products and their anticancer potential. Int. J. Mol. Sci.,  2017, 19(1), E13
[http://dx.doi.org/10.3390/ijms19010013] [PMID: 29267203] 
[89] 
Sun, L.; Wang, X. Effects of allicin on both telomerase activity and apoptosis in gastric cancer SGC-7901 cells. World J. Gastroenterol.,  2003, 9(9), 1930-1934.
[http://dx.doi.org/10.3748/wjg.v9.i9.1930] [PMID: 12970878] 
[90] 
Meeran, S.M.; Patel, S.N.; Tollefsbol, T.O. Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLoS One,  2010, 5(7), e11457
[http://dx.doi.org/10.1371/journal.pone.0011457] [PMID: 20625516] 
[91] 
Thelen, P.; Wuttke, W.; Jarry, H.; Grzmil, M.; Ringert, R.H. Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin in prostate cancer cells. J. Urol.,  2004, 171(5), 1934-1938.
[http://dx.doi.org/10.1097/01.ju.0000121329.37206.1b] [PMID: 15076315] 
[92] 
Nasiri, M.; Zarghami, N.; Koshki, K.N.; Mollazadeh, M.; Moghaddam, M.P.; Yamchi, M.R.; Esfahlan, R.J.; Barkhordari, A.; Alibakhshi, A. Curcumin and silibinin inhibit telomerase expression in T47D human breast cancer cells. Asian Pac. J. Cancer Prev.,  2013, 14(6), 3449-3453.
[http://dx.doi.org/10.7314/APJCP.2013.14.6.3449] [PMID: 23886126] 
[93] 
Lanzilli, G.; Fuggetta, M.P.; Tricarico, M.; Cottarelli, A.; Serafino, A.; Falchetti, R.; Ravagnan, G.; Turriziani, M.; Adamo, R.; Franzese, O.; Bonmassar, E. Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. Int. J. Oncol.,  2006, 28(3), 641-648.
[http://dx.doi.org/10.3892/ijo.28.3.641] [PMID: 16465368] 
[94] 
Mondal, A.; Chatterji, U. Artemisinin Represses Telomerase Subunits and Induces Apoptosis in HPV-39 Infected Human Cervical Cancer Cells. J. Cell. Biochem.,  2015, 116(9), 1968-1981.
[http://dx.doi.org/10.1002/jcb.25152] [PMID: 25755006] 
[95] 
Tippani, R.; Prakhya, L.J.; Porika, M.; Sirisha, K.; Abbagani, S.; Thammidala, C. Pterostilbene as a potential novel telomerase inhibitor: molecular docking studies and its in vitro evaluation. Curr. Pharm. Biotechnol.,  2014, 14(12), 1027-1035.
[http://dx.doi.org/10.2174/1389201015666140113112820] [PMID: 24433502] 
[96] 
Liu, Y.B.; Gao, X.; Deeb, D.; Pindolia, K.; Gautam, S.C. Role of telomerase in anticancer activity of pristimerin in prostate cancer cells. J. Exp. Ther. Oncol.,  2015, 11(1), 41-49.
[PMID: 26259389] 
[97] 
Park, S.E.; Park, C.; Kim, S.H.; Hossain, M.A.; Kim, M.Y.; Chung, H.Y.; Son, W.S.; Kim, G.Y.; Choi, Y.H.; Kim, N.D. Korean red ginseng extract induces apoptosis and decreases telomerase activity in human leukemia cells. J. Ethnopharmacol.,  2009, 121(2), 304-312.
[http://dx.doi.org/10.1016/j.jep.2008.10.038] [PMID: 19041934] 
[98] 
Moon, D.O.; Kang, C.H.; Kim, M.O.; Jeon, Y.J.; Lee, J.D.; Choi, Y.H.; Kim, G.Y. Beta-lapachone (LAPA) decreases cell viability and telomerase activity in leukemia cells: suppression of telomerase activity by LAPA. J. Med. Food,  2010, 13(3), 481-488.
[http://dx.doi.org/10.1089/jmf.2008.1219] [PMID: 20438329] 
[99] 
Royt, M.; Mukherjee, S.; Sarkar, R.; Biswas, J. Curcumin sensitizes chemotherapeutic drugs via modulation of PKC, telomerase, NF-kappaB and HDAC in breast cancer. Ther. Deliv.,  2011, 2(10), 1275-1293.
[http://dx.doi.org/10.4155/tde.11.97] [PMID: 22826883] 
[100] 
Lu, R.; O’Rourke, J.J.; Sobinoff, A.P.; Allen, J.A.M.; Nelson, C.B.; Tomlinson, C.G.; Lee, M.; Reddel, R.R.; Deans, A.J.; Pickett, H.A. The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT). Nat. Commun.,  2019, 10(1), 2252.
[http://dx.doi.org/10.1038/s41467-019-10180-6] [PMID: 31138797] 
[101] 
Alibakhshi, A.; Ranjbari, J.; Pilehvar-Soltanahmadi, Y.; Nasiri, M.; Mollazade, M.; Zarghami, N. An update on phytochemicals in molecular target therapy of cancer: potential inhibitory effect on telomerase activity. Curr. Med. Chem.,  2016, 23(22), 2380-2393.
[http://dx.doi.org/10.2174/0929867323666160425113705] [PMID: 27109576] 
[102] 
Lee, W.H.; Loo, C.Y.; Young, P.M.; Traini, D.; Mason, R.S.; Rohanizadeh, R. Recent advances in curcumin nanoformulation for cancer therapy. Expert Opin. Drug Deliv.,  2014, 11(8), 1183-1201.
[http://dx.doi.org/10.1517/17425247.2014.916686] [PMID: 24857605] 
[103] 
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(12), 6662-6667.
[http://dx.doi.org/10.1073/pnas.111464998] [PMID: 11371621] 
[104] 
Eitsuka, T.; Nakagawa, K.; Kato, S.; Ito, J.; Otoki, Y.; Takasu, S.; Shimizu, N.; Takahashi, T.; Miyazawa, T. Modulation of telomerase activity in cancer cells by dietary compounds: a review. Int. J. Mol. Sci.,  2018, 19(2), E478
[http://dx.doi.org/10.3390/ijms19020478] [PMID: 29415465] 
[105] 
Chau, M.N.; El Touny, L.H.; Jagadeesh, S.; Banerjee, P.P. Physiologically achievable concentrations of genistein enhance telomerase activity in prostate cancer cells via the activation of STAT3. Carcinogenesis,  2007, 28(11), 2282-2290.
[http://dx.doi.org/10.1093/carcin/bgm148] [PMID: 17615260] 
[106] 
Dragnev, K.H.; Rigas, J.R.; Dmitrovsky, E. The retinoids and cancer prevention mechanisms. Oncologist,  2000, 5(5), 361-368.
[http://dx.doi.org/10.1634/theoncologist.5-5-361] [PMID: 11040271] 
[107] 
Sharma, H.W.; Sokoloski, J.A.; Perez, J.R.; Maltese, J.Y.; Sartorelli, A.C.; Stein, C.A.; Nichols, G.; Khaled, Z.; Telang, N.T.; Narayanan, R. Differentiation of immortal cells inhibits telomerase activity. Proc. Natl. Acad. Sci. USA,  1995, 92(26), 12343-12346.
[http://dx.doi.org/10.1073/pnas.92.26.12343] [PMID: 8618897] 
[108] 
Love, W.K.; Berletch, J.B.; Andrews, L.G.; Tollefsbol, T.O. Epigenetic regulation of telomerase in retinoid-induced differentiation of human leukemia cells. Int. J. Oncol.,  2008, 32(3), 625-631.
[http://dx.doi.org/10.3892/ijo.32.3.625] [PMID: 18292940] 
[109] 
Pendino, F.; Dudognon, C.; Delhommeau, F.; Sahraoui, T.; Flexor, M.; Bennaceur-Griscelli, A.; Lanotte, M.; Ségal-Bendirdjian, E. Retinoic acid receptor alpha and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death. Oncogene,  2003, 22(57), 9142-9150.
[http://dx.doi.org/10.1038/sj.onc.1207093] [PMID: 14668795] 
[110] 
Ikeda, N.; Uemura, H.; Ishiguro, H.; Hori, M.; Hosaka, M.; Kyo, S.; Miyamoto, K.; Takeda, E.; Kubota, Y. Combination treatment with 1alpha,25-dihydroxyvitamin D3 and 9-cis-retinoic acid directly inhibits human telomerase reverse transcriptase transcription in prostate cancer cells. Mol. Cancer Ther.,  2003, 2(8), 739-746.
[PMID: 12939463] 
[111] 
Eitsuka, T.; Nakagawa, K.; Suzuki, T.; Miyazawa, T. Polyunsaturated fatty acids inhibit telomerase activity in DLD-1 human colorectal adenocarcinoma cells: a dual mechanism approach. Biochim. Biophys. Acta,  2005, 1737(1), 1-10.
[http://dx.doi.org/10.1016/j.bbalip.2005.08.017] [PMID: 16216547] 
[112] 
Tong, A.S.; Stern, J.L.; Sfeir, A.; Kartawinata, M.; de Lange, T.; Zhu, X.D.; Bryan, T.M. ATM and ATR Signaling regulate the recruitment of human telomerase to telomeres. Cell Rep.,  2015, 13(8), 1633-1646.
[http://dx.doi.org/10.1016/j.celrep.2015.10.041] [PMID: 26586433] 
[113] 
Cimprich, K.A.; Cortez, D. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol.,  2008, 9(8), 616-627.
[http://dx.doi.org/10.1038/nrm2450] [PMID: 18594563] 
[114] 
Reddy, V.; Wu, M.; Ciavattone, N.; McKenty, N.; Menon, M.; Barrack, E.R.; Reddy, G.P.; Kim, S.H. ATM inhibition potentiates death of androgen receptor-inactivated prostate cancer cells with telomere dysfunction. J. Biol. Chem.,  2015, 290(42), 25522-25533.
[http://dx.doi.org/10.1074/jbc.M115.671404] [PMID: 26336104] 
[115] 
Kwok, M.; Davies, N.; Agathanggelou, A.; Smith, E.; Oldreive, C.; Petermann, E.; Stewart, G.; Brown, J.; Lau, A.; Pratt, G.; Parry, H.; Taylor, M.; Moss, P.; Hillmen, P.; Stankovic, T. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood,  2016, 127(5), 582-595.
[http://dx.doi.org/10.1182/blood-2015-05-644872] [PMID: 26563132] 
[116] 
Batey, M.A.; Zhao, Y.; Kyle, S.; Richardson, C.; Slade, A.; Martin, N.M.; Lau, A.; Newell, D.R.; Curtin, N.J. Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer. Mol. Cancer Ther.,  2013, 12(6), 959-967.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0707] [PMID: 23512991] 
[117] 
Brandsma, I.; Fleuren, E.D.G.; Williamson, C.T.; Lord, C.J. Directing the use of DDR kinase inhibitors in cancer treatment. Expert Opin. Investig. Drugs,  2017, 26(12), 1341-1355.
[http://dx.doi.org/10.1080/13543784.2017.1389895] [PMID: 28984489] 
[118] 
Fokas, E.; Prevo, R.; Pollard, J.R.; Reaper, P.M.; Charlton, P.A.; Cornelissen, B.; Vallis, K.A.; Hammond, E.M.; Olcina, M.M.; Gillies McKenna, W.; Muschel, R.J.; Brunner, T.B. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis.,  2012, 3, e441
[http://dx.doi.org/10.1038/cddis.2012.181] [PMID: 23222511] 
[119] 
U. S. National Library of Medicine. First-in-human Study of ATR Inhibitor BAY1895344 in Patients With Advanced Solid Tumors and Lymphomas.,  Available from: 
                    clinicaltrials.gov/ct2/ show/NCT03188965
[120] 
Hickson, I.; Zhao, Y.; Richardson, C.J.; Green, S.J.; Martin, N.M.; Orr, A.I.; Reaper, P.M.; Jackson, S.P.; Curtin, N.J.; Smith, G.C. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res.,  2004, 64(24), 9152-9159.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2727] [PMID: 15604286] 
[121] 
Brown, J.S.; O’Carrigan, B.; Jackson, S.P.; Yap, T.A. Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov.,  2017, 7(1), 20-37.
[http://dx.doi.org/10.1158/2159-8290.CD-16-0860] [PMID: 28003236] 
[122] 
Jones, S.E.; Fleuren, E.D.G.; Frankum, J.; Konde, A.; Williamson, C.T.; Krastev, D.B.; Pemberton, H.N.; Campbell, J.; Gulati, A.; Elliott, R.; Menon, M.; Selfe, J.L.; Brough, R.; Pettitt, S.J.; Niedzwiedz, W.; van der Graaf, W.T.A.; Shipley, J.; Ashworth, A.; Lord, C.J. ATR is a therapeutic target in synovial sarcoma. Cancer Res.,  2017, 77(24), 7014-7026.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-2056] [PMID: 29038346] 
[123] 
 U. S. National Library of Medicine. Study to Assess the Safety and
Preliminary Efficacy of AZD0156 at Increasing Doses Alone or in
Combination With Other Anti-cancer Treatment in Patients With
Advanced Cancer (AToM). Available From: 
                    clinicaltrials.gov/ct2/show/NCT02588105
[124] 
Hannen, R.; Bartsch, J.W. Essential roles of telomerase reverse transcriptase hTERT in cancer stemness and metastasis. FEBS Lett.,  2018, 592(12), 2023-2031.
[http://dx.doi.org/10.1002/1873-3468.13084] [PMID: 29749098] 
[125] 
Leão, R.; Apolónio, J.D.; Lee, D.; Figueiredo, A.; Tabori, U.; Castelo-Branco, P. Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer. J. Biomed. Sci.,  2018, 25(1), 22.
[http://dx.doi.org/10.1186/s12929-018-0422-8] [PMID: 29526163] 
[126] 
Fletcher, T.M. Telomerase: a potential therapeutic target for cancer. Expert Opin. Ther. Targets,  2005, 9(3), 457-469.
[http://dx.doi.org/10.1517/14728222.9.3.457] [PMID: 15948667] 
[127] 
Lü, M.H.; Liao, Z.L.; Zhao, X.Y.; Fan, Y.H.; Lin, X.L.; Fang, D.C.; Guo, H.; Yang, S.M. hTERT-based therapy: a universal anticancer approach (Review). Oncol. Rep.,  2012, 28(6), 1945-1952.
[http://dx.doi.org/10.3892/or.2012.2036] [PMID: 22992764] 
[128] 
Sugarman, E.T.; Zhang, G.; Shay, J.W. In perspective: An update on telomere targeting in cancer. Mol. Carcinog.,  2019, 58(9), 1581-1588.
[http://dx.doi.org/10.1002/mc.23035] [PMID: 31062416] 
[129] 
Zhang, Y.; Toh, L.; Lau, P.; Wang, X. Human telomerase reverse transcriptase (hTERT) is a novel target of the Wnt/β-catenin pathway in human cancer. J. Biol. Chem.,  2012, 287(39), 32494-32511.
[http://dx.doi.org/10.1074/jbc.M112.368282] [PMID: 22854964] 
[130] 
Mender, I.; Gryaznov, S.; Dikmen, Z.G.; Wright, W.E.; Shay, J.W. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer Discov.,  2015, 5(1), 82-95.
[http://dx.doi.org/10.1158/2159-8290.CD-14-0609] [PMID: 25516420] 
[131] 
Frink, R.E.; Peyton, M.; Schiller, J.H.; Gazdar, A.F.; Shay, J.W.; Minna, J.D. Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner. Oncotarget,  2016, 7(22), 31639-31651.
[http://dx.doi.org/10.18632/oncotarget.9335] [PMID: 27192120] 
[132] 
El-Daly, H.; Kull, M.; Zimmermann, S.; Pantic, M.; Waller, C.F.; Martens, U.M. Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532. Blood,  2005, 105(4), 1742-1749.
[http://dx.doi.org/10.1182/blood-2003-12-4322] [PMID: 15507522] 
[133] 
Pascolo, E.; Wenz, C.; Lingner, J.; Hauel, N.; Priepke, H.; Kauffmann, I.; Garin-Chesa, P.; Rettig, W.J.; Damm, K.; Schnapp, A. Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate. J. Biol. Chem.,  2002, 277(18), 15566-15572.
[http://dx.doi.org/10.1074/jbc.M201266200] [PMID: 11854300] 
[134] 
Bashash, D.; Zareii, M.; Safaroghli-Azar, A.; Omrani, M.D.; Ghaffari, S.H. Inhibition of telomerase using BIBR1532 enhances doxorubicin-induced apoptosis in pre-B acute lymphoblastic leukemia cells. Hematology,  2017, 22(6), 330-340.
[http://dx.doi.org/10.1080/10245332.2016.1275426] [PMID: 28054503] 
[135] 
Bashash, D.; Ghaffari, S.H.; Zaker, F.; Kazerani, M.; Hezave, K.; Hassani, S.; Rostami, M.; Alimoghaddam, K.; Ghavamzadeh, A. BIBR 1532 increases arsenic trioxide-mediated apoptosis in acute promyelocytic leukemia cells: therapeutic potential for APL. Anticancer. Agents Med. Chem.,  2013, 13(7), 1115-1125.
[http://dx.doi.org/10.2174/18715206113139990126] [PMID: 23293885] 
[136] 
Shi, Y.; Sun, L.; Chen, G.; Zheng, D.; Li, L.; Wei, W. A combination of the telomerase inhibitor, BIBR1532, and paclitaxel synergistically inhibit cell proliferation in breast cancer cell lines. Target. Oncol.,  2015, 10(4), 565-573.
[http://dx.doi.org/10.1007/s11523-015-0364-y] [PMID: 25916999] 
[137] 
Mender, I.; Gryaznov, S.; Shay, J.W. A novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells. Oncoscience,  2015, 2(8), 693-695.
[http://dx.doi.org/10.18632/oncoscience.213] [PMID: 26425659] 
[138] 
Saraswati, A.P.; Relitti, N.; Brindisi, M.; Gemma, S.; Zisterer, D.; Butini, S.; Campiani, G. Raising the bar in anticancer therapy: recent advances in, and perspectives on, telomerase inhibitors. Drug Discov. Today,  2019, 24(7), 1370-1388.
[http://dx.doi.org/10.1016/j.drudis.2019.05.015] [PMID: 31136800] 
[139] 
Fagerberg, L.; Hallström, B.M.; Oksvold, P.; Kampf, C.; Djureinovic, D.; Odeberg, J.; Habuka, M.; Tahmasebpoor, S.; Danielsson, A.; Edlund, K.; Asplund, A.; Sjöstedt, E.; Lundberg, E.; Szigyarto, C.A.; Skogs, M.; Takanen, J.O.; Berling, H.; Tegel, H.; Mulder, J.; Nilsson, P.; Schwenk, J.M.; Lindskog, C.; Danielsson, F.; Mardinoglu, A.; Sivertsson, A.; von Feilitzen, K.; Forsberg, M.; Zwahlen, M.; Olsson, I.; Navani, S.; Huss, M.; Nielsen, J.; Ponten, F.; Uhlén, M. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell. Proteomics,  2014, 13(2), 397-406.
[http://dx.doi.org/10.1074/mcp.M113.035600] [PMID: 24309898] 
[140] 
De Vitis, M.; Berardinelli, F.; Sgura, A. Telomere length maintenance in cancer: at the crossroad between telomerase and alternative lengthening of telomeres (ALT). Int. J. Mol. Sci.,  2018, 19(2), E606
[http://dx.doi.org/10.3390/ijms19020606] [PMID: 29463031] 
[141] 
Greider, C.W. Telomeres do D-loop-T-loop. Cell,  1999, 97(4), 419-422.
[http://dx.doi.org/10.1016/S0092-8674(00)80750-3] [PMID: 10338204] 
[142] 
Zhong, Z.; Shiue, L.; Kaplan, S.; de Lange, T. A mammalian factor that binds telomeric TTAGGG repeats in vitro. Mol. Cell. Biol.,  1992, 12(11), 4834-4843.
[http://dx.doi.org/10.1128/MCB.12.11.4834] [PMID: 1406665] 
[143] 
Broccoli, D.; Smogorzewska, A.; Chong, L.; de Lange, T. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat. Genet.,  1997, 17(2), 231-235.
[http://dx.doi.org/10.1038/ng1097-231] [PMID: 9326950] 
[144] 
van Steensel, B.; de Lange, T. Control of telomere length by the human telomeric protein TRF1. Nature,  1997, 385(6618), 740-743.
[http://dx.doi.org/10.1038/385740a0] [PMID: 9034193] 
[145] 
Diotti, R.; Loayza, D. Shelterin complex and associated factors at human telomeres. Nucleus,  2011, 2(2), 119-135.
[http://dx.doi.org/10.4161/nucl.2.2.15135] [PMID: 21738835] 
[146] 
Takai, K.K.; Hooper, S.; Blackwood, S.; Gandhi, R.; de Lange, T. In vivo stoichiometry of shelterin components. J. Biol. Chem.,  2010, 285(2), 1457-1467.
[http://dx.doi.org/10.1074/jbc.M109.038026] [PMID: 19864690] 
[147] 
Li, H.L.; Song, J.; Yong, H.M.; Hou, P.F.; Chen, Y.S.; Song, W.B.; Bai, J.; Zheng, J.N. PinX1: structure, regulation and its functions in cancer. Oncotarget,  2016, 7(40), 66267-66275.
[http://dx.doi.org/10.18632/oncotarget.11411] [PMID: 27556185] 
[148] 
Soohoo, C.Y.; Shi, R.; Lee, T.H.; Huang, P.; Lu, K.P.; Zhou, X.Z. Telomerase inhibitor PinX1 provides a link between TRF1 and telomerase to prevent telomere elongation. J. Biol. Chem.,  2011, 286(5), 3894-3906.
[http://dx.doi.org/10.1074/jbc.M110.180174] [PMID: 21119197] 
[149] 
Zhou, X.Z.; Lu, K.P. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell,  2001, 107(3), 347-359.
[http://dx.doi.org/10.1016/S0092-8674(01)00538-4] [PMID: 11701125] 
[150] 
Sfeir, A. Telomeres at a glance. J. Cell Sci.,  2012, 125(Pt 18), 4173-4178.
[http://dx.doi.org/10.1242/jcs.106831] [PMID: 23135002] 
[151] 
Nakamura, M.; Zhou, X.Z.; Kishi, S.; Lu, K.P. Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle. FEBS Lett.,  2002, 514(2-3), 193-198.
[http://dx.doi.org/10.1016/S0014-5793(02)02363-3] [PMID: 11943150] 
[152] 
Kishi, S.; Zhou, X.Z.; Ziv, Y.; Khoo, C.; Hill, D.E.; Shiloh, Y.; Lu, K.P. Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. J. Biol. Chem.,  2001, 276(31), 29282-29291.
[http://dx.doi.org/10.1074/jbc.M011534200] [PMID: 11375976] 
[153] 
Nosaka, K.; Kawahara, M.; Masuda, M.; Satomi, Y.; Nishino, H. Association of nucleoside diphosphate kinase nm23-H2 with human telomeres. Biochem. Biophys. Res. Commun.,  1998, 243(2), 342-348.
[http://dx.doi.org/10.1006/bbrc.1997.8097] [PMID: 9480811] 
[154] 
Netzer, C.; Rieger, L.; Brero, A.; Zhang, C.D.; Hinzke, M.; Kohlhase, J.; Bohlander, S.K. SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin. Hum. Mol. Genet.,  2001, 10(26), 3017-3024.
[http://dx.doi.org/10.1093/hmg/10.26.3017] [PMID: 11751684] 
[155] 
Kelland, L. Targeting the limitless replicative potential of cancer: the telomerase/telomere pathway. Clin. Cancer Res.,  2007, 13(17), 4960-4963.
[156] 
Cherfils-Vicini, J.; Gilson, E. Inhibiting TRF1 upstream signaling pathways to target telomeres in cancer cells. EMBO Mol. Med.,  2019, 11(7), e10845
[http://dx.doi.org/10.15252/emmm.201910845] [PMID: 31273935] 
[157] 
Bejarano, L.; Schuhmacher, A.J.; Méndez, M.; Megías, D.; Blanco-Aparicio, C.; Martínez, S.; Pastor, J.; Squatrito, M.; Blasco, M.A. Inhibition of TRF1 telomere protein impairs tumor initiation and progression in glioblastoma mouse models and patient-derived xenografts. Cancer Cell,  2017, 32(5), 590-607.
[http://dx.doi.org/10.1016/j.ccell.2017.10.006] 
[158] 
García-Beccaria, M.; Martínez, P.; Méndez-Pertuz, M.; Martínez, S.; Blanco-Aparicio, C.; Cañamero, M.; Mulero, F.; Ambrogio, C.; Flores, J.M.; Megias, D.; Barbacid, M.; Pastor, J.; Blasco, M.A. Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage. EMBO Mol. Med.,  2015, 7(7), 930-949.
[http://dx.doi.org/10.15252/emmm.201404497] [PMID: 25971796] 
[159] 
Bejarano, L.; Bosso, G.; Louzame, J.; Serrano, R.; Gómez-Casero, E.; Martínez-Torrecuadrada, J.; Martínez, S.; Blanco-Aparicio, C.; Pastor, J.; Blasco, M.A. Multiple cancer pathways regulate telomere protection. EMBO Mol. Med.,  2019, 11(7), e10292
[http://dx.doi.org/10.15252/emmm.201910292] [PMID: 31273934] 
[160] 
Bilsland, A.E.; Cairney, C.J.; Keith, W.N. Targeting the telomere and shelterin complex for cancer therapy: current views and future perspectives. J. Cell. Mol. Med.,  2011, 15(2), 179-186.
[http://dx.doi.org/10.1111/j.1582-4934.2010.01253.x] [PMID: 21199331] 
[161] 
de Lange, T. Shelterin-mediated telomere protection. Annu. Rev. Genet.,  2018, 52, 223-247.
[http://dx.doi.org/10.1146/annurev-genet-032918-021921] [PMID: 30208292] 
[162] 
Karlseder, J.; Hoke, K.; Mirzoeva, O.K.; Bakkenist, C.; Kastan, M.B.; Petrini, J.H.; de Lange, T. The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol.,  2004, 2(8), E240
[http://dx.doi.org/10.1371/journal.pbio.0020240] [PMID: 15314656] 
[163] 
Martínez, P.; Blasco, M.A. Telomere-driven diseases and telomere-targeting therapies. J. Cell Biol.,  2017, 216(4), 875-887.
[http://dx.doi.org/10.1083/jcb.201610111] [PMID: 28254828] 
[164] 
Zaug, A.J.; Podell, E.R.; Cech, T.R. Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proc. Natl. Acad. Sci. USA,  2005, 102(31), 10864-10869.
[http://dx.doi.org/10.1073/pnas.0504744102] [PMID: 16043710] 
[165] 
Kelleher, C.; Kurth, I.; Lingner, J. Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol. Cell. Biol.,  2005, 25(2), 808-818.
[http://dx.doi.org/10.1128/MCB.25.2.808-818.2005] [PMID: 15632080] 
[166] 
Wang, F.; Podell, E.R.; Zaug, A.J.; Yang, Y.; Baciu, P.; Cech, T.R.; Lei, M. The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature,  2007, 445(7127), 506-510.
[http://dx.doi.org/10.1038/nature05454] [PMID: 17237768] 
[167] 
Yang, D.; Okamoto, K. Structural insights into G-quadruplexes: towards new anticancer drugs. Future Med. Chem.,  2010, 2(4), 619-646.
[http://dx.doi.org/10.4155/fmc.09.172] [PMID: 20563318] 
[168] 
Shalaby, T.; Fiaschetti, G.; Nagasawa, K.; Shin-ya, K.; Baumgartner, M.; Grotzer, M. G-quadruplexes as potential therapeutic targets for embryonal tumors. Molecules,  2013, 18(10), 12500-12537.
[http://dx.doi.org/10.3390/molecules181012500] [PMID: 24152672] 
[169] 
Churikov, D.; Wei, C.; Price, C.M. Vertebrate POT1 restricts G-overhang length and prevents activation of a telomeric DNA damage checkpoint but is dispensable for overhang protection. Mol. Cell. Biol.,  2006, 26(18), 6971-6982.
[http://dx.doi.org/10.1128/MCB.01011-06] [PMID: 16943437] 
[170] 
Kondo, T.; Oue, N.; Yoshida, K.; Mitani, Y.; Naka, K.; Nakayama, H.; Yasui, W. Expression of POT1 is associated with tumor stage and telomere length in gastric carcinoma. Cancer Res.,  2004, 64(2), 523-529.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-1196] [PMID: 14744765] 
[171] 
Zhou, H.; Mondal, A.; Dakic, A.; Alhawas, L.; Liu, X.; He, Z. Time-dependent effects of POT1 knockdown on proliferation, tumorigenicity, and HDACi response of SK-OV3 ovarian cancer cells. BioMed Res. Int.,  2018, 2018, 7184253
[http://dx.doi.org/10.1155/2018/7184253] [PMID: 29546066] 
[172] 
Deng, Y.; Chan, S.S.; Chang, S. Telomere dysfunction and tumour suppression: the senescence connection. Nat. Rev. Cancer,  2008, 8(6), 450-458.
[http://dx.doi.org/10.1038/nrc2393] [PMID: 18500246] 
[173] 
Takai, H.; Jenkinson, E.; Kabir, S.; Babul-Hirji, R.; Najm-Tehrani, N.; Chitayat, D.A.; Crow, Y.J.; de Lange, T. A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus. Genes Dev.,  2016, 30(7), 812-826.
[http://dx.doi.org/10.1101/gad.276873.115] [PMID: 27013236] 
[174] 
Pinzaru, A.M.; Hom, R.A.; Beal, A.; Phillips, A.F.; Ni, E.; Cardozo, T.; Nair, N.; Choi, J.; Wuttke, D.S.; Sfeir, A.; Denchi, E.L. Telomere replication stress induced by POT1 inactivation accelerates tumorigenesis. Cell Rep.,  2016, 15(10), 2170-2184.
[http://dx.doi.org/10.1016/j.celrep.2016.05.008] [PMID: 27239034] 
[175] 
Gu, P.; Wang, Y.; Bisht, K.K.; Wu, L.; Kukova, L.; Smith, E.M.; Xiao, Y.; Bailey, S.M.; Lei, M.; Nandakumar, J.; Chang, S. Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis. Oncogene,  2017, 36(14), 1939-1951.
[http://dx.doi.org/10.1038/onc.2016.405] [PMID: 27869160] 
[176] 
Altschuler, S.E.; Croy, J.E.; Wuttke, D.S. A small molecule inhibitor of Pot1 binding to telomeric DNA. Biochemistry,  2012, 51(40), 7833-7845.
[http://dx.doi.org/10.1021/bi300365k] [PMID: 22978652] 
[177] 
Gomez, D.; O’Donohue, M.F.; Wenner, T.; Douarre, C.; Macadré, J.; Koebel, P.; Giraud-Panis, M.J.; Kaplan, H.; Kolkes, A.; Shin-ya, K.; Riou, J.F. The G-quadruplex ligand telomestatin inhibits POT1 binding to telomeric sequences in vitro and induces GFP-POT1 dissociation from telomeres in human cells. Cancer Res.,  2006, 66(14), 6908-6912.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1581] [PMID: 16849533] 
[178] 
Rajavel, M.; Mullins, M.R.; Taylor, D.J. Multiple facets of TPP1 in telomere maintenance. Biochim. Biophys. Acta,  2014, 1844(9), 1550-1559.
[http://dx.doi.org/10.1016/j.bbapap.2014.04.014] [PMID: 24780581] 
[179] 
Rice, C.; Shastrula, P.K.; Kossenkov, A.V.; Hills, R.; Baird, D.M.; Showe, L.C.; Doukov, T.; Janicki, S.; Skordalakes, E. Structural and functional analysis of the human POT1-TPP1 telomeric complex. Nat. Commun.,  2017, 8, 14928.
[http://dx.doi.org/10.1038/ncomms14928] [PMID: 28393830] 
[180] 
Grill, S.; Tesmer, V.M.; Nandakumar, J. The N terminus of the OB domain of telomere protein TPP1 is critical for telomerase action. Cell Rep.,  2018, 22(5), 1132-1140.
[http://dx.doi.org/10.1016/j.celrep.2018.01.012] [PMID: 29386102] 
[181] 
Chen, C.; Gu, P.; Wu, J.; Chen, X.; Niu, S.; Sun, H.; Wu, L.; Li, N.; Peng, J.; Shi, S.; Fan, C.; Huang, M.; Wong, C.C.; Gong, Q.; Kumar-Sinha, C.; Zhang, R.; Pusztai, L.; Rai, R.; Chang, S.; Lei, M. Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat. Commun.,  2017, 8, 14929.
[http://dx.doi.org/10.1038/ncomms14929] [PMID: 28393832] 
[182] 
Nandakumar, J.; Bell, C.F.; Weidenfeld, I.; Zaug, A.J.; Leinwand, L.A.; Cech, T.R. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature,  2012, 492(7428), 285-289.
[http://dx.doi.org/10.1038/nature11648] [PMID: 23103865] 
[183] 
Dalby, A.B.; Hofr, C.; Cech, T.R. Contributions of the TEL-patch amino acid cluster on TPP1 to telomeric DNA synthesis by human telomerase. J. Mol. Biol.,  2015, 427(6 Pt B), 1291-1303.
[http://dx.doi.org/10.1016/j.jmb.2015.01.008] [PMID: 25623306] 
[184] 
Nakashima, M.; Nandakumar, J.; Sullivan, K.D.; Espinosa, J.M.; Cech, T.R. Inhibition of telomerase recruitment and cancer cell death. J. Biol. Chem.,  2013, 288(46), 33171-33180.
[http://dx.doi.org/10.1074/jbc.M113.518175] [PMID: 24097987] 
[185] 
Zhong, F.L.; Batista, L.F.; Freund, A.; Pech, M.F.; Venteicher, A.S.; Artandi, S.E. TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell,  2012, 150(3), 481-494.
[http://dx.doi.org/10.1016/j.cell.2012.07.012] [PMID: 22863003] 
[186] 
Zhu, J.; Liu, W.; Chen, C.; Zhang, H.; Yue, D.; Li, C.; Zhang, L.; Gao, L.; Huo, Y.; Liu, C.; Giaccone, G.; Zhang, B.; Wang, C. TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells. J. Cancer Res. Clin. Oncol.,  2019, 145(6), 1509-1519.
[http://dx.doi.org/10.1007/s00432-019-02921-3] [PMID: 31016380] 
[187] 
Hall, B.M.; Balan, V.; Gleiberman, A.S.; Strom, E.; Krasnov, P.; Virtuoso, L.P.; Rydkina, E.; Vujcic, S.; Balan, K.; Gitlin, I.; Leonova, K.; Polinsky, A.; Chernova, O.B.; Gudkov, A.V. Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY),  2016, 8(7), 1294-1315.
[http://dx.doi.org/10.18632/aging.100991] [PMID: 27391570] 
[188] 
Newman, M.R.; Benoit, D.S.W. In vivo translation of peptide-targeted drug delivery systems discovered by phage Display. Bioconjug. Chem.,  2018, 29(7), 2161-2169.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00285] [PMID: 29889510] 
[189] 
Dissanayake, S.; Denny, W.A.; Gamage, S.; Sarojini, V. Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides. J. Control. Release,  2017, 250, 62-76.
[http://dx.doi.org/10.1016/j.jconrel.2017.02.006] [PMID: 28167286] 
[190] 
Wang, Y.; Cheetham, A.G.; Angacian, G.; Su, H.; Xie, L.; Cui, H. Peptide-drug conjugates as effective prodrug strategies for targeted delivery. Adv. Drug Deliv. Rev.,  2017, 110-111, 112-126.
[http://dx.doi.org/10.1016/j.addr.2016.06.015] [PMID: 27370248] 
[191] 
Zeng, X.; Hernandez-Sanchez, W.; Xu, M.; Whited, T.L.; Baus, D.; Zhang, J.; Berdis, A.J.; Taylor, D.J. Administration of a nucleoside analog promotes cancer cell death in a telomerase-dependent manner. Cell Rep.,  2018, 23(10), 3031-3041.
[http://dx.doi.org/10.1016/j.celrep.2018.05.020] [PMID: 29874588] 
[192] 
Flynn, R.L.; Chang, S.; Zou, L. RPA and POT1: friends or foes at telomeres? Cell Cycle,  2012, 11(4), 652-657.
[http://dx.doi.org/10.4161/cc.11.4.19061] [PMID: 22373525] 
[193] 
Lin, C.; Yang, D. Human telomeric G-quadruplex structures and G-quadruplex-interactive compounds. Methods Mol. Biol.,  2017, 1587, 171-196.
[http://dx.doi.org/10.1007/978-1-4939-6892-3_17] [PMID: 28324509] 
[194] 
Maizels, N. Dynamic roles for G4 DNA in the biology of eukaryotic cells. Nat. Struct. Mol. Biol.,  2006, 13(12), 1055-1059.
[http://dx.doi.org/10.1038/nsmb1171] [PMID: 17146462] 
[195] 
Rhodes, D.; Lipps, H.J. G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res.,  2015, 43(18), 8627-8637.
[http://dx.doi.org/10.1093/nar/gkv862] [PMID: 26350216] 
[196] 
Arnoult, N.; Saintome, C.; Ourliac-Garnier, I.; Riou, J.F.; Londoño-Vallejo, A. Human POT1 is required for efficient telomere C-rich strand replication in the absence of WRN. Genes Dev.,  2009, 23(24), 2915-2924.
[http://dx.doi.org/10.1101/gad.544009] [PMID: 20008939] 
[197] 
Punchihewa, C.Y.D. Therapeutic Targets and Drugs II: G-Quadruplex and G-Quadruplex Inhibitors; Hiyama, K., Ed.; Humana Press, 2009, p. 380.
[198] 
Tauchi, T.; Shin-ya, K.; Sashida, G.; Sumi, M.; Okabe, S.; Ohyashiki, J.H.; Ohyashiki, K. Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia. Oncogene,  2006, 25(42), 5719-5725.
[http://dx.doi.org/10.1038/sj.onc.1209577] [PMID: 16652154] 
[199] 
Burger, A.M.; Dai, F.; Schultes, C.M.; Reszka, A.P.; Moore, M.J.; Double, J.A.; Neidle, S. The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res.,  2005, 65(4), 1489-1496.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2910] [PMID: 15735037] 
[200] 
Gunaratnam, M.; Greciano, O.; Martins, C.; Reszka, A.P.; Schultes, C.M.; Morjani, H.; Riou, J.F.; Neidle, S. Mechanism of acridine-based telomerase inhibition and telomere shortening. Biochem. Pharmacol.,  2007, 74(5), 679-689.
[http://dx.doi.org/10.1016/j.bcp.2007.06.011] [PMID: 17631279] 
[201] 
Cookson, J.C.; Dai, F.; Smith, V.; Heald, R.A.; Laughton, C.A.; Stevens, M.F.; Burger, A.M. Pharmacodynamics of the G-quadruplex-stabilizing telomerase inhibitor 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) in vitro: activity in human tumor cells correlates with telomere length and can be enhanced, or antagonized, with cytotoxic agents. Mol. Pharmacol.,  2005, 68(6), 1551-1558.
[http://dx.doi.org/10.1124/mol.105.013300] [PMID: 16150933] 
[202] 
Sobinoff, A.P.; Allen, J.A.; Neumann, A.A.; Yang, S.F.; Walsh, M.E.; Henson, J.D.; Reddel, R.R.; Pickett, H.A. BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres. EMBO J.,  2017, 36(19), 2907-2919.
[http://dx.doi.org/10.15252/embj.201796889] [PMID: 28877996] 
[203] 
Monchaud, D.; Granzhan, A.; Saettel, N.; Guédin, A.; Mergny, J.L.; Teulade-Fichou, M.P. “One ring to bind them all”-part I: the efficiency of the macrocyclic scaffold for g-quadruplex DNA recognition. J. Nucleic Acids,  2010, pii: 525862.
[http://dx.doi.org/10.4061/2010/525862] 
[204] 
Gomez, D.L.; Armando, R.G.; Cerrudo, C.S.; Ghiringhelli, P.D.; Gomez, D.E. Telomerase as a cancer target. development of new molecules. Curr. Top. Med. Chem.,  2016, 16(22), 2432-2440.
[http://dx.doi.org/10.2174/1568026616666160212122425] [PMID: 26873194] 
[205] 
Temime-Smaali, N.; Guittat, L.; Sidibe, A.; Shin-ya, K.; Trentesaux, C.; Riou, J.F. The G-quadruplex ligand telomestatin impairs binding of topoisomerase IIIalpha to G-quadruplex-forming oligonucleotides and uncaps telomeres in ALT cells. PLoS One,  2009, 4(9), e6919
[http://dx.doi.org/10.1371/journal.pone.0006919] [PMID: 19742304] 
[206] 
Tahara, H.; Shin-Ya, K.; Seimiya, H.; Yamada, H.; Tsuruo, T.; Ide, T. G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells. Oncogene,  2006, 25(13), 1955-1966.
[http://dx.doi.org/10.1038/sj.onc.1209217] [PMID: 16302000] 
[207] 
Miyazaki, T.; Pan, Y.; Joshi, K.; Purohit, D.; Hu, B.; Demir, H.; Mazumder, S.; Okabe, S.; Yamori, T.; Viapiano, M.; Shin-ya, K.; Seimiya, H.; Nakano, I. Telomestatin impairs glioma stem cell survival and growth through the disruption of telomeric G-quadruplex and inhibition of the proto-oncogene, c-Myb. Clin. Cancer Res.,  2012, 18(5), 1268-1280.
[208] 
Kim, S.J.; McAlpine, S.R. Solid phase versus solution phase synthesis of heterocyclic macrocycles. Molecules,  2013, 18(1), 1111-1121.
[http://dx.doi.org/10.3390/molecules18011111] [PMID: 23325099] 
[209] 
Sullivan, H.J.; Readmond, C.; Radicella, C.; Persad, V.; Fasano, T.J.; Wu, C. Binding of telomestatin, TMPyP4, BSU6037 and BRACO19 to a telomeric g-quadruplex-duplex hybrid probed by all-atom molecular dynamics simulations with explicit solvent. ACS Omega,  2018, 3(11), 14788-14806.
[http://dx.doi.org/10.1021/acsomega.8b01574] [PMID: 30555989] 
[210] 
Gowan, S.M.; Harrison, J.R.; Patterson, L.; Valenti, M.; Read, M.A.; Neidle, S.; Kelland, L.R. A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol. Pharmacol.,  2002, 61(5), 1154-1162.
[http://dx.doi.org/10.1124/mol.61.5.1154] [PMID: 11961134] 
[211] 
Haider, S.M.; Neidle, S. A molecular model for drug binding to tandem repeats of telomeric G-quadruplexes. Biochem. Soc. Trans.,  2009, 37(Pt 3), 583-588.
[http://dx.doi.org/10.1042/BST0370583] [PMID: 19442254] 
[212] 
Taetz, S.; Baldes, C.; Mürdter, T.E.; Kleideiter, E.; Piotrowska, K.; Bock, U.; Haltner-Ukomadu, E.; Mueller, J.; Huwer, H.; Schaefer, U.F.; Klotz, U.; Lehr, C.M. Biopharmaceutical characterization of the telomerase inhibitor BRACO19. Pharm. Res.,  2006, 23(5), 1031-1037.
[http://dx.doi.org/10.1007/s11095-006-0026-y] [PMID: 16715394] 
[213] 
Dilley, R.L.; Verma, P.; Cho, N.W.; Winters, H.D.; Wondisford, A.R.; Greenberg, R.A. Break-induced telomere synthesis underlies alternative telomere maintenance. Nature,  2016, 539(7627), 54-58.
[http://dx.doi.org/10.1038/nature20099] [PMID: 27760120] 
[214] 
Henson, J.D.; Hannay, J.A.; McCarthy, S.W.; Royds, J.A.; Yeager, T.R.; Robinson, R.A.; Wharton, S.B.; Jellinek, D.A.; Arbuckle, S.M.; Yoo, J.; Robinson, B.G.; Learoyd, D.L.; Stalley, P.D.; Bonar, S.F.; Yu, D.; Pollock, R.E.; Reddel, R.R. A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin. Cancer Res.,  2005, 11(1), 217-225.
[PMID: 15671549] 
[215] 
Sanders, R.P.; Drissi, R.; Billups, C.A.; Daw, N.C.; Valentine, M.B.; Dome, J.S. Telomerase expression predicts unfavorable outcome in osteosarcoma. J. Clin. Oncol.,  2004, 22(18), 3790-3797.
[http://dx.doi.org/10.1200/JCO.2004.03.043] [PMID: 15365076] 
[216] 
Hu, Y.; Shi, G.; Zhang, L.; Li, F.; Jiang, Y.; Jiang, S.; Ma, W.; Zhao, Y.; Songyang, Z.; Huang, J. Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX. Sci. Rep.,  2016, 6, 32280.
[http://dx.doi.org/10.1038/srep32280] [PMID: 27578458] 
[217] 
Bechter, O.E.; Zou, Y.; Walker, W.; Wright, W.E.; Shay, J.W. Telomeric recombination in mismatch repair deficient human colon cancer cells after telomerase inhibition. Cancer Res.,  2004, 64(10), 3444-3451.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0323] [PMID: 15150096] 
[218] 
Chen, W.; Chen, S.M.; Yu, Y.; Xiao, B.K.; Huang, Z.W.; Tao, Z.Z. Telomerase inhibition alters telomere maintenance mechanisms in laryngeal squamous carcinoma cells. J. Laryngol. Otol.,  2010, 124(7), 778-783.
[http://dx.doi.org/10.1017/S0022215109992854] [PMID: 20403221] 
[219] 
O’Sullivan, R.J.; Arnoult, N.; Lackner, D.H.; Oganesian, L.; Haggblom, C.; Corpet, A.; Almouzni, G.; Karlseder, J. Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1. Nat. Struct. Mol. Biol.,  2014, 21(2), 167-174.
[http://dx.doi.org/10.1038/nsmb.2754] [PMID: 24413054] 
[220] 
Heaphy, C.M.; de Wilde, R.F.; Jiao, Y.; Klein, A.P.; Edil, B.H.; Shi, C.; Bettegowda, C.; Rodriguez, F.J.; Eberhart, C.G.; Hebbar, S.; Offerhaus, G.J.; McLendon, R.; Rasheed, B.A.; He, Y.; Yan, H.; Bigner, D.D.; Oba-Shinjo, S.M.; Marie, S.K.; Riggins, G.J.; Kinzler, K.W.; Vogelstein, B.; Hruban, R.H.; Maitra, A.; Papadopoulos, N.; Meeker, A.K. Altered telomeres in tumors with ATRX and DAXX mutations. Science,  2011, 333(6041), 425.
[http://dx.doi.org/10.1126/science.1207313] [PMID: 21719641] 
[221] 
Schwartzentruber, J.; Korshunov, A.; Liu, X.Y.; Jones, D.T.; Pfaff, E.; Jacob, K.; Sturm, D.; Fontebasso, A.M.; Quang, D.A.; Tönjes, M.; Hovestadt, V.; Albrecht, S.; Kool, M.; Nantel, A.; Konermann, C.; Lindroth, A.; Jäger, N.; Rausch, T.; Ryzhova, M.; Korbel, J.O.; Hielscher, T.; Hauser, P.; Garami, M.; Klekner, A.; Bognar, L.; Ebinger, M.; Schuhmann, M.U.; Scheurlen, W.; Pekrun, A.; Frühwald, M.C.; Roggendorf, W.; Kramm, C.; Dürken, M.; Atkinson, J.; Lepage, P.; Montpetit, A.; Zakrzewska, M.; Zakrzewski, K.; Liberski, P.P.; Dong, Z.; Siegel, P.; Kulozik, A.E.; Zapatka, M.; Guha, A.; Malkin, D.; Felsberg, J.; Reifenberger, G.; von Deimling, A.; Ichimura, K.; Collins, V.P.; Witt, H.; Milde, T.; Witt, O.; Zhang, C.; Castelo-Branco, P.; Lichter, P.; Faury, D.; Tabori, U.; Plass, C.; Majewski, J.; Pfister, S.M.; Jabado, N. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature,  2012, 482(7384), 226-231.
[http://dx.doi.org/10.1038/nature10833] [PMID: 22286061] 
[222] 
Cheung, N.K.; Zhang, J.; Lu, C.; Parker, M.; Bahrami, A.; Tickoo, S.K.; Heguy, A.; Pappo, A.S.; Federico, S.; Dalton, J.; Cheung, I.Y.; Ding, L.; Fulton, R.; Wang, J.; Chen, X.; Becksfort, J.; Wu, J.; Billups, C.A.; Ellison, D.; Mardis, E.R.; Wilson, R.K.; Downing, J.R.; Dyer, M.A. St Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA,  2012, 307(10), 1062-1071.
[http://dx.doi.org/10.1001/jama.2012.228] [PMID: 22416102] 
[223] 
Lovejoy, C.A.; Li, W.; Reisenweber, S.; Thongthip, S.; Bruno, J.; de Lange, T.; De, S.; Petrini, J.H.; Sung, P.A.; Jasin, M.; Rosenbluh, J.; Zwang, Y.; Weir, B.A.; Hatton, C.; Ivanova, E.; Macconaill, L.; Hanna, M.; Hahn, W.C.; Lue, N.F.; Reddel, R.R.; Jiao, Y.; Kinzler, K.; Vogelstein, B.; Papadopoulos, N.; Meeker, A.K.; Consortium, A.L.T.S.C. ALT Starr Cancer Consortium. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet.,  2012, 8(7), e1002772
[http://dx.doi.org/10.1371/journal.pgen.1002772] [PMID: 22829774] 
[224] 
Shay, J.W.; Reddel, R.R.; Wright, W.E. Cancer. Cancer and telomeres--an ALTernative to telomerase. Science,  2012, 336(6087), 1388-1390.
[http://dx.doi.org/10.1126/science.1222394] [PMID: 22700908] 
[225] 
Cesare, A.J.; Reddel, R.R. Alternative lengthening of telomeres: models, mechanisms and implications. Nat. Rev. Genet.,  2010, 11(5), 319-330.
[http://dx.doi.org/10.1038/nrg2763] [PMID: 20351727] 
[226] 
Chhabra, G.; Wojdyla, L.; Frakes, M.; Schrank, Z.; Leviskas, B.; Ivancich, M.; Vinay, P.; Ganapathy, R.; Ramirez, B.E.; Puri, N. Mechanism of action of g-quadruplex-forming oligonucleotide homologous to the telomere overhang in Melanoma. J. Invest. Dermatol.,  2018, 138(4), 903-910.
[http://dx.doi.org/10.1016/j.jid.2017.11.021] [PMID: 29203363] 
[227] 
Longe, H.O.; Romesser, P.B.; Rankin, A.M.; Faller, D.V.; Eller, M.S.; Gilchrest, B.A.; Denis, G.V. Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential. Int. J. Cancer,  2009, 124(2), 473-482.
[http://dx.doi.org/10.1002/ijc.23946] [PMID: 19003960] 
[228] 
Yaar, M.; Eller, M.S.; Panova, I.; Kubera, J.; Wee, L.H.; Cowan, K.H.; Gilchrest, B.A. Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells. Breast Cancer Res.,  2007, 9(1), R13.
[http://dx.doi.org/10.1186/bcr1646] [PMID: 17257427] 
[229] 
Wojdyla, L.; Stone, A.L.; Sethakorn, N.; Uppada, S.B.; Devito, J.T.; Bissonnette, M.; Puri, N. T-oligo as an anticancer agent in colorectal cancer. Biochem. Biophys. Res. Commun.,  2014, 446(2), 596-601.
[http://dx.doi.org/10.1016/j.bbrc.2014.03.013] [PMID: 24632202] 
[230] 
Puri, N.; Eller, M.S.; Byers, H.R.; Dykstra, S.; Kubera, J.; Gilchrest, B.A. Telomere-based DNA damage responses: a new approach to melanoma. FASEB J.,  2004, 18(12), 1373-1381.
[http://dx.doi.org/10.1096/fj.04-1774com] [PMID: 15333580] 
[231] 
Uppada, S.B.; Erickson, T.; Wojdyla, L.; Moravec, D.N.; Song, Z.; Cheng, J.; Puri, N. Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy. Int. J. Nanomedicine,  2014, 9, 43-53.
[PMID: 24391441] 
[232] 
Mulnix, R.E.; Pitman, R.T.; Retzer, A.; Bertram, C.; Arasi, K.; Crees, Z.; Girard, J.; Uppada, S.B.; Stone, A.L.; Puri, N. hnRNP C1/C2 and Pur-beta proteins mediate induction of senescence by oligonucleotides homologous to the telomere overhang. OncoTargets Ther.,  2013, 7, 23-32.
[PMID: 24379680] 
[233] 
Pitman, R.T.; Wojdyla, L.; Puri, N. Mechanism of DNA damage responses induced by exposure to an oligonucleotide homologous to the telomere overhang in melanoma. Oncotarget,  2013, 4(5), 761-771.
[http://dx.doi.org/10.18632/oncotarget.1047] [PMID: 23800953] 
[234] 
Puri, N.; Pitman, R.T.; Mulnix, R.E.; Erickson, T.; Iness, A.N.; Vitali, C.; Zhao, Y.; Salgia, R. Non-small cell lung cancer is susceptible to induction of DNA damage responses and inhibition of angiogenesis by telomere overhang oligonucleotides. Cancer Lett.,  2014, 343(1), 14-23.
[http://dx.doi.org/10.1016/j.canlet.2013.09.010] [PMID: 24041868] 
[235] 
Wellinger, R.J. Turning telomerase into a Jekyll and Hyde case? Cancer Discov.,  2015, 5(1), 19-21.
[http://dx.doi.org/10.1158/2159-8290.CD-14-1346] [PMID: 25583799] 
[236] 
Zhang, G.; Wu, L.W.; Mender, I.; Barzily-Rokni, M.; Hammond, M.R.; Ope, O.; Cheng, C.; Vasilopoulos, T.; Randell, S.; Sadek, N.; Beroard, A.; Xiao, M.; Tian, T.; Tan, J.; Saeed, U.; Sugarman, E.; Krepler, C.; Brafford, P.; Sproesser, K.; Murugan, S.; Somasundaram, R.; Garman, B.; Wubbenhorst, B.; Woo, J.; Yin, X.; Liu, Q.; Frederick, D.T.; Miao, B.; Xu, W.; Karakousis, G.C.; Xu, X.; Schuchter, L.M.; Mitchell, T.C.; Kwong, L.N.; Amaravadi, R.K.; Lu, Y.; Boland, G.M.; Wei, Z.; Nathanson, K.; Herbig, U.; Mills, G.B.; Flaherty, K.T.; Herlyn, M.; Shay, J.W. Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma. Clin. Cancer Res.,  2018, 24(19), 4771-4784.
[237] 
Mender, I.; LaRanger, R.; Luitel, K.; Peyton, M.; Girard, L.; Lai, T.P.; Batten, K.; Cornelius, C.; Dalvi, M.P.; Ramirez, M.; Du, W.; Wu, L.F.; Altschuler, S.J.; Brekken, R.; Martinez, E.D.; Minna, J.D.; Wright, W.E.; Shay, J.W. Telomerase-mediated strategy for overcoming non-small cell lung cancer targeted therapy and chemotherapy resistance. Neoplasia,  2018, 20(8), 826-837.
[http://dx.doi.org/10.1016/j.neo.2018.06.002] [PMID: 30015158] 
[238] 
Sengupta, S.; Sobo, M.; Lee, K.; Senthil Kumar, S.; White, A.R.; Mender, I.; Fuller, C.; Chow, L.M.L.; Fouladi, M.; Shay, J.W.; Drissi, R. Induced telomere damage to treat telomerase expressing therapy-resistant pediatric brain tumors. Mol. Cancer Ther.,  2018, 17(7), 1504-1514.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0792] [PMID: 29654065] 
[239] 
Seimiya, H.; Muramatsu, Y.; Ohishi, T.; Tsuruo, T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell,  2005, 7(1), 25-37.
[http://dx.doi.org/10.1016/j.ccr.2004.11.021] [PMID: 15652747] 
[240] 
Riffell, J.L.; Lord, C.J.; Ashworth, A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat. Rev. Drug Discov.,  2012, 11(12), 923-936.
[http://dx.doi.org/10.1038/nrd3868] [PMID: 23197039] 
[241] 
Seimiya, H.; Muramatsu, Y.; Smith, S.; Tsuruo, T. Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation. Mol. Cell. Biol.,  2004, 24(5), 1944-1955.
[http://dx.doi.org/10.1128/MCB.24.5.1944-1955.2004] [PMID: 14966275] 
[242] 
Cook, B.D.; Dynek, J.N.; Chang, W.; Shostak, G.; Smith, S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol. Cell. Biol.,  2002, 22(1), 332-342.
[http://dx.doi.org/10.1128/MCB.22.1.332-342.2002] [PMID: 11739745] 
[243] 
Hsiao, S.J.; Smith, S. Tankyrase function at telomeres, spindle poles, and beyond. Biochimie,  2008, 90(1), 83-92.
[http://dx.doi.org/10.1016/j.biochi.2007.07.012] [PMID: 17825467] 
[244] 
Ha, G.H.; Kim, H.S.; Go, H.; Lee, H.; Seimiya, H.; Chung, D.H.; Lee, C.W. Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation. Cell Death Differ.,  2012, 19(2), 321-332.
[http://dx.doi.org/10.1038/cdd.2011.101] [PMID: 21818122] 
[245] 
Waaler, J.; Machon, O.; Tumova, L.; Dinh, H.; Korinek, V.; Wilson, S.R.; Paulsen, J.E.; Pedersen, N.M.; Eide, T.J.; Machonova, O.; Gradl, D.; Voronkov, A.; von Kries, J.P.; Krauss, S. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res.,  2012, 72(11), 2822-2832.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-3336] [PMID: 22440753] 
[246] 
Tian, X.H.; Hou, W.J.; Fang, Y.; Fan, J.; Tong, H.; Bai, S.L.; Chen, Q.; Xu, H.; Li, Y. XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway. J. Exp. Clin. Cancer Res.,  2013, 32, 100.
[http://dx.doi.org/10.1186/1756-9966-32-100] [PMID: 24308762] 
[247] 
Huang, S.M.; Mishina, Y.M.; Liu, S.; Cheung, A.; Stegmeier, F.; Michaud, G.A.; Charlat, O.; Wiellette, E.; Zhang, Y.; Wiessner, S.; Hild, M.; Shi, X.; Wilson, C.J.; Mickanin, C.; Myer, V.; Fazal, A.; Tomlinson, R.; Serluca, F.; Shao, W.; Cheng, H.; Shultz, M.; Rau, C.; Schirle, M.; Schlegl, J.; Ghidelli, S.; Fawell, S.; Lu, C.; Curtis, D.; Kirschner, M.W.; Lengauer, C.; Finan, P.M.; Tallarico, J.A.; Bouwmeester, T.; Porter, J.A.; Bauer, A.; Cong, F. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature,  2009, 461(7264), 614-620.
[http://dx.doi.org/10.1038/nature08356] [PMID: 19759537] 
[248] 
Dregalla, R.C.; Zhou, J.; Idate, R.R.; Battaglia, C.L.; Liber, H.L.; Bailey, S.M. Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs. Aging (Albany NY),  2010, 2(10), 691-708.
[http://dx.doi.org/10.18632/aging.100210] [PMID: 21037379] 
[249] 
Lu, H.; Lei, Z.; Lu, Z.; Lu, Q.; Lu, C.; Chen, W.; Wang, C.; Tang, Q.; Kong, Q. Silencing tankyrase and telomerase promotes A549 human lung adenocarcinoma cell apoptosis and inhibits proliferation. Oncol. Rep.,  2013, 30(4), 1745-1752.
[http://dx.doi.org/10.3892/or.2013.2665] [PMID: 23933993] 
[250] 
Holt, S.E.; Aisner, D.L.; Baur, J.; Tesmer, V.M.; Dy, M.; Ouellette, M.; Trager, J.B.; Morin, G.B.; Toft, D.O.; Shay, J.W.; Wright, W.E.; White, M.A. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev.,  1999, 13(7), 817-826.
[http://dx.doi.org/10.1101/gad.13.7.817] [PMID: 10197982] 
[251] 
Barran, L.R.; Ritchot, N.; Bromfield, E.S. Sinorhizobium meliloti plasmid pRm1132f replicates by a rolling-circle mechanism. J. Bacteriol.,  2001, 183(8), 2704-2708.
[http://dx.doi.org/10.1128/JB.183.8.2704-2708.2001] [PMID: 11274136] 
[252] 
Sauvage, F.; Messaoudi, S.; Fattal, E.; Barratt, G.; Vergnaud-Gauduchon, J. Heat shock proteins and cancer: How can nanomedicine be harnessed? J. Control. Release,  2017, 248, 133-143.
[http://dx.doi.org/10.1016/j.jconrel.2017.01.013] [PMID: 28088573] 
[253] 
Garg, G.; Khandelwal, A.; Blagg, B.S. Anticancer inhibitors of Hsp90 function: beyond the usual suspects. Adv. Cancer Res.,  2016, 129, 51-88.
[http://dx.doi.org/10.1016/bs.acr.2015.12.001] [PMID: 26916001] 
[254] 
Morimoto, R.I. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev.,  1998, 12(24), 3788-3796.
[http://dx.doi.org/10.1101/gad.12.24.3788] [PMID: 9869631] 
[255] 
Keppler, B.R.; Grady, A.T.; Jarstfer, M.B. The biochemical role of the heat shock protein 90 chaperone complex in establishing human telomerase activity. J. Biol. Chem.,  2006, 281(29), 19840-19848.
[http://dx.doi.org/10.1074/jbc.M511067200] [PMID: 16714764] 
[256] 
Taipale, M.; Krykbaeva, I.; Koeva, M.; Kayatekin, C.; Westover, K.D.; Karras, G.I.; Lindquist, S. Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell,  2012, 150(5), 987-1001.
[http://dx.doi.org/10.1016/j.cell.2012.06.047] [PMID: 22939624] 
[257] 
DeZwaan, D.C.; Toogun, O.A.; Echtenkamp, F.J.; Freeman, B.C. The Hsp82 molecular chaperone promotes a switch between unextendable and extendable telomere states. Nat. Struct. Mol. Biol.,  2009, 16(7), 711-716.
[http://dx.doi.org/10.1038/nsmb.1616] [PMID: 19525972] 
[258] 
Mel, B.W. Have we been hebbing down the wrong path? Neuron,  2002, 34(2), 175-177.
[http://dx.doi.org/10.1016/S0896-6273(02)00669-4] [PMID: 11970858] 
[259] 
Toogun, O.A.; Dezwaan, D.C.; Freeman, B.C. The hsp90 molecular chaperone modulates multiple telomerase activities. Mol. Cell. Biol.,  2008, 28(1), 457-467.
[http://dx.doi.org/10.1128/MCB.01417-07] [PMID: 17954556] 
[260] 
Miyata, Y.; Nakamoto, H.; Neckers, L. The therapeutic target Hsp90 and cancer hallmarks. Curr. Pharm. Des.,  2013, 19(3), 347-365.
[http://dx.doi.org/10.2174/138161213804143725] [PMID: 22920906] 
[261] 
Mizuno, H.; Khurts, S.; Seki, T.; Hirota, Y.; Kaneko, S.; Murakami, S. Human telomerase exists in two distinct active complexes in vivo. J. Biochem.,  2007, 141(5), 641-652.
[http://dx.doi.org/10.1093/jb/mvm071] [PMID: 17383981] 
[262] 
Kim, R.H.; Kim, R.; Chen, W.; Hu, S.; Shin, K.H.; Park, N.H.; Kang, M.K. Association of hsp90 to the hTERT promoter is necessary for hTERT expression in human oral cancer cells. Carcinogenesis,  2008, 29(12), 2425-2431.
[http://dx.doi.org/10.1093/carcin/bgn225] [PMID: 18820283] 
[263] 
Miyata, Y. Hsp90 inhibitor geldanamycin and its derivatives as novel cancer chemotherapeutic agents. Curr. Pharm. Des.,  2005, 11(9), 1131-1138.
[http://dx.doi.org/10.2174/1381612053507585] [PMID: 15853661] 
[264] 
Samuni, Y.; Ishii, H.; Hyodo, F.; Samuni, U.; Krishna, M.C.; Goldstein, S.; Mitchell, J.B. Reactive oxygen species mediate hepatotoxicity induced by the Hsp90 inhibitor geldanamycin and its analogs. Free Radic. Biol. Med.,  2010, 48(11), 1559-1563.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.03.001] [PMID: 20211249] 
[265] 
Kim, Y.S.; Alarcon, S.V.; Lee, S.; Lee, M.J.; Giaccone, G.; Neckers, L.; Trepel, J.B. Update on Hsp90 inhibitors in clinical trial. Curr. Top. Med. Chem.,  2009, 9(15), 1479-1492.
[http://dx.doi.org/10.2174/156802609789895728] [PMID: 19860730] 
[266] 
Arteaga, C.L. Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer? Clin. Cancer Res.,  2011, 17(15), 4919-4921.
[267] 
The Myeloma Beacon. Bristol-Myers Squibb Halts Development of Tanespimycin.,  Available on 
                    https://myelomabeacon.org/news/ 2010/07/22/tanespimycin-development-halted/
[268] 
U. S. National Library of Medicine. Geldanamycin Search Results. Available on, https://clinicaltrials.gov/ct2/results?cond=&term=Geldanamycin&cntry=&state=&city=&dist
[269] 
Jhaveri, K.; Ochiana, S.O.; Dunphy, M.P.; Gerecitano, J.F.; Corben, A.D.; Peter, R.I.; Janjigian, Y.Y.; Gomes-DaGama, E.M.; Koren, J., III; Modi, S.; Chiosis, G. Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert Opin. Investig. Drugs,  2014, 23(5), 611-628.
[http://dx.doi.org/10.1517/13543784.2014.902442] [PMID: 24669860] 
[270] 
Delmotte, P.; Delmotte-Plaque, J. A new antifungal substance of fungal origin. Nature,  1953, 171(4347), 344.
[http://dx.doi.org/10.1038/171344a0] [PMID: 13036885] 
[271] 
Chiosis, G.; Kang, Y.; Sun, W. Discovery and development of purine-scaffold Hsp90 inhibitors. Expert Opin. Drug Discov.,  2008, 3(1), 99-114.
[http://dx.doi.org/10.1517/17460441.3.1.99] [PMID: 23480142] 
[272] 
Yan, L.; Zhang, W.; Zhang, B.; Xuan, C.; Wang, D. BIIB021: A novel inhibitor to heat shock protein 90-addicted oncology. Tumour Biol.,  2017, 39(4), 1010428317698355
[http://dx.doi.org/10.1177/1010428317698355] [PMID: 28443462] 
[273] 
Wang, X.T.; Bao, C.H.; Jia, Y.B.; Wang, N.; Ma, W.; Liu, F.; Wang, C.; Wang, J.B.; Song, Q.X.; Cheng, Y.F. BIIB021, a novel Hsp90 inhibitor, sensitizes esophageal squamous cell carcinoma to radiation. Biochem. Biophys. Res. Commun.,  2014, 452(4), 945-950.
[http://dx.doi.org/10.1016/j.bbrc.2014.09.026] [PMID: 25223594] 
[274] 
Yin, X.; Zhang, H.; Lundgren, K.; Wilson, L.; Burrows, F.; Shores, C.G. BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy. Int. J. Cancer,  2010, 126(5), 1216-1225.
[PMID: 19662650] 
[275] 
Wang, H.; Lu, M.; Yao, M.; Zhu, W. Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials. Mol. Clin. Oncol.,  2016, 5(3), 326-334.
[http://dx.doi.org/10.3892/mco.2016.963] [PMID: 27602225] 
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DOI https://dx.doi.org/10.2174/1568026620666200109114339	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294
Current Topics in Medicinal Chemistry

Potential Telomere-Related Pharmacological Targets

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