Treating Cancer by Targeting Telomeres and Telomerase

Abstract

Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effe...

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

“…Telomeres and telomerase are key biological structures for supporting cancer cell proliferation since cancer cells can bypass the lifespan limits of normal cells by overexpressing telomerase (Telomerase +), or by using the alternative mechanism of telomere elongation (ALT+ cells). Hence, targeting telomeres or telomerase has been classically considered as a strategy for developing cancer therapies (7). In the present study, we have confirmed that TH5487 block BER initiation at telomeres in response to OS, and…”

“…Cancer cells are characterized by preserving stable telomere length, thereby conferring cell immortality (6). In consequence, the induction of telomeric instability is considered as a potential therapeutic strategy for cancer treatment (7).…”

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

“…3 Then, telomerase inhibition has become a new potential therapeutic approach. 7,8 Telomerase activity is also associated with resistance to specific drugs, as Imatinib. 6 Whereas this enzyme is generally absent in normal cells and plays a crucial role in tumour ones, it is a good target for new drugs development.…”

“…6 Whereas this enzyme is generally absent in normal cells and plays a crucial role in tumour ones, it is a good target for new drugs development. 7,8 Telomerase activity is also associated with resistance to specific drugs, as Imatinib. 9 The anti-tumour potential of many telomerase inhibitors has been investigated, [10][11][12][13][14] but the effects of long-term treatment with these drugs on tumour cells remain not well understood.…”

Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells

“…The paradigm that cancer cells are immortal was often linked with the statement that they proliferate indefinitely and avoid senescence due to active telomerase or alternative mechanisms of telomere lengthening [4]. For this reason, telomerase became a tempting target in experimental anti-cancer therapy [100]. The truth is, however, far more complex, which is evidenced by multiple observations that senescence may be triggered in cancer cells by their exposure to clinically relevant doses of ionizing radiation (radiotherapy) and chemotherapy [101].…”