**6. Abbreviations**

evidence for the CSC concept. As summarised in this chapter, telomerase contributes to carcinogenesis most likely through the emergence and persistence of conspicuous CSC qualities. Accordingly, telomerase inhibition in CSCs is predicted to: (i) shrink telomeres; (ii) restrain anchorage-independent growth and inhibit proliferation by cell cycle arrest; (iii) induce CSC death; (iv) induce CSC differentiation; (v) inhibit CSC migration and reverse the EMT programme; (vi) deteriorate glucose metabolism; (vii) enhance radio- and chemosensi‐ tivity; and (viii) disrupt the CSC niche. Serious telomere shrinkage is assumed to be a longterm effect of telomerase inhibition in CSCs so the tumour mass will continue to expand for a time after treatment until its constituent cells enter crisis and begin to die in large numbers. The rest of the aforementioned effects, however, are likely to occur after short-term exposure of CSCs to telomerase inhibitors, inducing relatively rapid initial responses to treatment. Natural telomerase inhibitors (phytochemicals) and small-molecule telomerase inhibitors, antisense oligonucleotides and chemically modified nucleic acids, immunotherapeutic agents, and telomerase-directed gene therapy are promising treatment options and may play a larger role in the near future [130]. Imetelstat (GRN163L), which was designed by Geron Corporation in 2003, is the first telomerase inhibitor to advance to clinical development. It is a lipidconjugated 13-mer (5'‒TAGGGTTAGACAA‒3') antisense oligonucleotide that is complemen‐ tary to and binds with high affinity to TER, thereby directly inhibiting telomerase activity and interfering with telomere length homeostasis. It is perhaps safe here to assume that Imetelstat impairs the regulatory role of telomerase in CSC biology not only through telomere shortening but also through negatively influencing its telomere length-independent tumour-promoting functions. In support of this, short-term (72-hour) Imetelstat exposure was shown to promote the differentiation and inhibit the colony-forming ability of multiple myeloma CSCs through a telomere length-independent mechanism [131]. Similarly, *in vitro* Imetelstat treatment was found to deplete breast and pancreatic CSCs, as measured by the reduced proportion of ALDHpositive and CSC-surface marker-expressing cells, through a mechanism of action independ‐ ent of telomere shortening [132]. Although Imetelstat is known to form thermodynamically stable and sequence-specific duplexes with TER, the possibility that even less thermodynam‐ ically stable tetraplexes of Imetelstat may bind to and interfere with some other, yet to be identified, proteins (particularly those that interact with telomerase) should not be excluded [133]. There also exists a possibility that telomerase inhibitors like Imetelstat may be coupled with conventional therapies such as surgical (debulking) therapy, radiotherapy, and chemo‐ therapy, all of which have their own weaknesses and inadequacies. Such combination therapy is predicted to result in rapid and durable clinical responses in broad tumour types (Figure 3). As shown by the sources provided earlier in this chapter and elsewhere in the literature, the principal signalling pathways governing CSC biology operate in physiological stem cells as well. This complicates telomerase inhibition therapy because of the risk of telomerase inhibitors exerting an adverse influence on the size of the physiological stem cell pool and/or on the integrity of the physiological stem cell niche. The notion that physiological stem cells only transiently express telomerase and have relatively long telomeres [65], however, means that there is likely to be a narrow but safe therapeutic window where only CSCs will be depleted by telomerase inhibitors and normal stem cells will remain unaffected. Furthermore, rational approaches that disrupt the interactions of telomerase with important downstream components of embryonic/oncogenic signalling pathways (Wnt/β-catenin and NF-κB being the most prominent of all so far) may be conceived and executed as therapeutic tactics to

202 Telomere - A Complex End of a Chromosome

ABC, ATP-binding cassette; Akt, protein kinase B; ALDH1, aldehyde dehydrogenase 1; BAX, BCL-2-associated protein X; BCL, B-cell lymphoma family protein; BMI-1, B lymphoma Mo-MLV insertion region 1 homolog; BMP, bone morphogenetic protein; BRG1, Brahma-related gene 1; CD, cluster of differentiation; CHK, checkpoint kinase; COX-2, cyclooxygenase-2; CXCR4, C–X–C chemokine receptor type 4; EGFR, epidermal growth factor receptor; ERK1/2, extracellular signal-related kinase 1/2; FAK, focal adhesion kinase; GLUTs, glucose transport‐ ers; GNL3L, guanine nucleotide-binding protein-like 3-like; IL, interleukin; ITGB1, integrin beta-1; JAK, Janus kinase; KLF-4, Kruppel-like factor-4; MAC2BP, Mac-2-binding protein; MCL-1, myeloid cell leukaemia-1; MIC-1, macrophage inhibitory cytokine-1; MMPs, matrix metalloproteinases; MYC, v-myc avian myelocytomatosis viral oncoprotein homolog; mTOR, mammalian target of rapamycin; NANOG, Nanog homeobox transcription factor; NF-κB, nuclear factor-κB; NS, nucleostemin; OCT-3/4, octamer-binding transcription factor-3/4; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; SDF-1, stromal cellderived factor-1; SMAD, small mother against decapentaplegic homolog; SNAI, snail family zinc-finger transcription factor; SOX-2, SRY (sex determining region Y)-box 2; STAT, signal transducer and activator of transcription; TAZ, Tafazzin; TGF-β, transforming growth factorβ; TNF-α, tumour necrosis factor-α; TWIST, twist family bHLH (basic helix-loop-helix) transcription factor; VEGF, vascular endothelial growth factor; Wnt, Wingless ligand; YAP, Yes-associated protein; ZEB, zinc-finger E-box-binding homeobox family protein

## **Author details**

Kerem Teralı1\* and Açelya Yilmazer2

\*Address all correspondence to: kerem.terali@neu.edu.tr

1 Department of Medical Biochemistry, Faculty of Medicine, Near East University, Nicosia, North Cyprus, via Mersin, Turkey

2 Department of Biomedical Engineering, Faculty of Engineering, Ankara University, Tandogan, Ankara, Turkey

## **References**


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CXCR4, C–X–C chemokine receptor type 4; EGFR, epidermal growth factor receptor; ERK1/2, extracellular signal-related kinase 1/2; FAK, focal adhesion kinase; GLUTs, glucose transport‐ ers; GNL3L, guanine nucleotide-binding protein-like 3-like; IL, interleukin; ITGB1, integrin beta-1; JAK, Janus kinase; KLF-4, Kruppel-like factor-4; MAC2BP, Mac-2-binding protein; MCL-1, myeloid cell leukaemia-1; MIC-1, macrophage inhibitory cytokine-1; MMPs, matrix metalloproteinases; MYC, v-myc avian myelocytomatosis viral oncoprotein homolog; mTOR, mammalian target of rapamycin; NANOG, Nanog homeobox transcription factor; NF-κB, nuclear factor-κB; NS, nucleostemin; OCT-3/4, octamer-binding transcription factor-3/4; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; SDF-1, stromal cellderived factor-1; SMAD, small mother against decapentaplegic homolog; SNAI, snail family zinc-finger transcription factor; SOX-2, SRY (sex determining region Y)-box 2; STAT, signal transducer and activator of transcription; TAZ, Tafazzin; TGF-β, transforming growth factorβ; TNF-α, tumour necrosis factor-α; TWIST, twist family bHLH (basic helix-loop-helix) transcription factor; VEGF, vascular endothelial growth factor; Wnt, Wingless ligand; YAP,

Yes-associated protein; ZEB, zinc-finger E-box-binding homeobox family protein

1 Department of Medical Biochemistry, Faculty of Medicine, Near East University, Nicosia,

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