AZT as a telomerase inhibitor

Daniel E Gomez,Romina G Armando,Daniel F Alonso

doi:10.3389/fonc.2012.00113

Abstract

Telomerase is a highly specialized reverse transcriptase (RT) and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic RT prompted studies of inhibiting telomerase with the HIV RT inhibitor azidothymidine (AZT). Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence, and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

Highlights

Telomerase is a ribonucleoprotein that elongates the telomeres in eukaryotic cells
Based on experiments in fibroblasts, in the absence of telomerase, cellular telomeres are seen to shorten with an increasing number of cell divisions
Bodnar et al (1996) showed that the reintroduction of the catalytic compound of telomerase in primary human fibroblasts and endothelial cells that lack telomerase activity elongated the telomeric repetitions resulting in significant increases in replicative cell life

Summary

Introduction

Telomerase is a ribonucleoprotein that elongates the telomeres in eukaryotic cells. The enzyme is composed of a catalytic subunit, hTERT, a RNA component, hTR, and a group of associated proteins. Bodnar et al (1996) showed that the reintroduction of the catalytic compound of telomerase in primary human fibroblasts and endothelial cells that lack telomerase activity elongated the telomeric repetitions resulting in significant increases in replicative cell life. Telomerase activity is found in most immortalized cell lines and in 85–90% of human tumors.

Results

Conclusion