Radiolabeled oligonucleotides targeting the RNA subunit of telomerase inhibit telomerase and induce DNA damage in telomerase-positive cancer cells

Jackson, M. R. , Bavelaar, B. M., Waghorn, P. A., Gill, M. R., El-Sagheer, A. H., Brown, T., Tarsounas, M. and Vallis, K. A. (2019) Radiolabeled oligonucleotides targeting the RNA subunit of telomerase inhibit telomerase and induce DNA damage in telomerase-positive cancer cells. Cancer Research, 79(18), pp. 4627-4637. (doi: 10.1158/0008-5472.CAN-18-3594) (PMID:31311806)

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Abstract

Telomerase is expressed in the majority (>85%) of tumours, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterisation of radiolabeled oligonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic activity and delivering radiation intracellularly. Oligonucleotides complementary (match) and non-complementary (scramble or mismatch) to hTR were conjugated to diethylenetriaminepentaacetic dianhydride (DTPA), allowing radiolabeling with the Auger electron-emitting radionuclide indium-111 (111In). Match oligonucleotides inhibited telomerase activity with high potency which was not observed with scramble or mismatch oligonucleotides. DTPA-conjugation and 111In-labeling did not change telomerase inhibition. In telomerase-positive cancer cells, unlabeled match oligonucleotides had no effect on survival, however, 111In-labeled match oligonucleotides significantly reduced clonogenic survival and upregulated the DNA damage marker γH2AX. Minimal radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to 111In-match oligonucleotides. Match oligonucleotides localised in close proximity to nuclear Cajal bodies in telomerase-positive cells. In comparison to match oligonucleotides, 111In-scramble or 111In-mismatch oligonucleotides demonstrated reduced retention and negligible impact on cell survival. This study indicates the therapeutic activity of radiolabeled oligonucleotides that specifically target hTR through potent telomerase inhibition and DNA damage induction in telomerase-expressing cancer cells, and paves way for the development of novel oligonucleotide radiotherapeutics targeting telomerase-positive cancers.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jackson, Dr Mark
Authors: Jackson, M. R., Bavelaar, B. M., Waghorn, P. A., Gill, M. R., El-Sagheer, A. H., Brown, T., Tarsounas, M., and Vallis, K. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:16 July 2019
Copyright Holders:Copyright © 2019 American Association for Cancer Research
First Published:First published in Cancer Research 79(18):4627-4637
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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