Telomerase and its potential for therapeutic intervention

Abstract

Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation--a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed.

Figure 1

Consequences of telomerase enzyme inhibition compared to direct telomere targeting. ‘Pure' enzyme inhibitors require a lag time (several cell divisions) before telomeres shorten to a critical length. This process is slow and depends on the initial telomere length. Cell death is predominately caused by cellular senescence. Telomere targeting agents, such as G-quadruplex ligands, uncap telomeres and induce a p53-independent telomere-associated DNA-damage response. This process is fast and can induce senescence as well as apoptosis.

Figure 2

(a) The telomere cap is composed of telomerase and telomere-associated proteins as well as telomeric DNA repair proteins (see also Table 1). The 3′-end of telomeric DNA must be single-stranded for hybridization with hTERC. (b) G-quadruplex ligands (TTA, red) induce the 3′-end overhang to fold into a quadruplex structure, which inhibits hTERT and hTERC binding and stops telomere elongation. Unbound telomerase and telomere proteins (Pot1, Hsp90, etc.) translocate into the cytoplasm and undergo degradation via the ubiquitin (Ub) proteasome system (e.g. hTERT). ‘Unprotected' telomeres signal DNA damage, a very early indicator of this is the phosphorylation of H2AX and, thus, formation of γ-H2AX foci in nuclei of affected cells (Phatak et al., 2007; Salvati et al., 2007). Ligands need to be selective for this higher-order G-quadruplex structure to have minimal duplex DNA affinity so that drug concentrations that inhibit the enzyme activity to 50% (telEC50) << general cellular cytotoxicity. TTA, telomere targeting agent.

Figure 3

Molecular structures of telomerase inhibitory agents. (a) GRN163L, (b) BIBR1532, (c) BRACO19, (d) RHPS4 and (e) telomestatin.