Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Abstract

SUMMARY Telomerase, the end-replication enzyme, is reactivated in malignant cancers to drive cellular immortality. While this distinction makes telomerase an attractive target for anti-cancer therapies, most approaches for inhibiting its activity have been clinically ineffective. As opposed to inhibiting telomerase, we use its activity to selectively promote cytotoxicity in cancer cells. We show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU) triphosphate, are effectively incorporated by telomerase into a telomere DNA product. Administration of 5-FdU results in an increased number of telomere-induced foci, impedes binding of telomere proteins, activates the ATR-related DNA-damage response, and promotes cell death in a telomerase-dependent manner. Collectively, our data indicate that telomerase activity can be exploited as a putative anti-cancer strategy.

Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting to telomere

“…Many telomerase inhibitors has thus been developed to treat cancers; however, none of them becomes the applicable clinical drugs due to their side effects [59][60][61]. On the other hand, a recent study indicated that the telomeric DNA damage could promote cancer cell death [62]. Therefore, we targeted telomere DNA to induce cancer cell death by Nage vector in this study.…”

Ratiometric Electrochemical Sensing Strategy for the Ultrasensitive Detection of Telomerase Activity

“…Human telomerase is a ribonucleoprotein complex with an endogenous RNA template, which catalyzes the extension of hexamer DNA repeats . In a majority of human cancers, telomerase is upregulated or reactivated, which leads to indefinite proliferation of cancer cells . Telomerase is now a critical marker for early diagnosis of cancer .…”

Expanding the chemotherapeutic potential of an established nucleoside analog with selective targeting of telomerase

“…Our approach centers on the ability of telomerase to misincorporate toxic nucleoside analogs, specifically 5-fluoro-2ʹdeoxyuridine (5-FdU), into telomeric DNA thereby compromising telomere integrity to induce cell death (Figure 1). 5 This mechanism of telomerase-dependent misincorporation leads to a disruption of binding interactions at the telomere essential for maintaining telomere stability. 5 The loss of essential protein-DNA complexes at compromised telomeres initiates illicit DNA damage response and eventual cell death in a telomerase-dependent manner.…”

“…5 This mechanism of telomerase-dependent misincorporation leads to a disruption of binding interactions at the telomere essential for maintaining telomere stability. 5 The loss of essential protein-DNA complexes at compromised telomeres initiates illicit DNA damage response and eventual cell death in a telomerase-dependent manner. 5 The expansion of telomeric-based inhibitors to include "Trojan horse" therapeutics provides a resolution for the disadvantages associated with conventional approaches to telomerase inhibition.…”

“…5 The loss of essential protein-DNA complexes at compromised telomeres initiates illicit DNA damage response and eventual cell death in a telomerase-dependent manner. 5 The expansion of telomeric-based inhibitors to include "Trojan horse" therapeutics provides a resolution for the disadvantages associated with conventional approaches to telomerase inhibition. If this mechanism translates in vivo, such a telomerase-targeted approach presents several therapeutic advantages that could revive the feasibility of telomeric-based chemotherapies.…”