Báo cáo khoa học: Human telomeric G-quadruplex: The current status of telomeric G-quadruplexes as

MINIREVIEW

Human telomeric G-quadruplex: The current status

of telomeric G-quadruplexes as therapeutic targets

in human cancer

Stephen Neidle

Cancer Research UK Biomolecular Structure Group, University of London, UK

Introduction

Human telomeres comprise tandem repeats of the

DNA motif (TTAGGG) together with associated telo￾meric proteins [1–3], as well as other more transiently

associated DNA-repair and damage-response proteins

such as Ku [4]. The terminal 150–250 nucleotides at

the extreme 3¢-ends of telomeres are single-stranded

[5], but are protected from higher order aggregation by

binding to multiple repeats of a single-stranded DNA

binding protein (hPOT1 in humans), which in turn

interacts with other proteins in the core telomere

complex, notably TPP1, to regulate telomerase action

in cancer cells, and thereby maintain telomere length

[6–8]. Loss of hPOT1 deprotects telomeres and initiates

DNA damage-response mediated cell death. Small

molecules that stabilize the single strand into higher

order (G-quadruplex) structures compete with hPOT1

and also initiate this response [9–11]. Thus, quadruplex

formation at the single-strand overhang may itself be a

DNA damage signal, producing responses analogous

to those of other mediators of telomere damage [12].

The biological function of induced telomeric quadru￾plexes remains to be fully clarified; an end-protective

role has been suggested, there is evidence of functional

interactions involving poly(ADP-ribose) polymerase-1

[13] and in ciliates at least, quadruplex structures are

involved in telomerase recruitment [14,15]. However,

to date, there is no direct evidence of a role for telo￾meric G-quadruplexes in the functioning of telomeres

in normal human cells.

Telomerase is overexpressed in 80–85% of cancer

cells and primary tumours [16,17] and maintains

telomere length homeostatis (acting as a tumour

promoter). Telomere shortening in the absence of sig￾nificant telomerase expression appears to be a tumour

suppressor mechanism [3]. Telomeres in telomerase￾negative somatic cells are gradually shortened as a

Keywords

acridine; anticancer; drug; drug-like; in vivo;

medicinal chemistry; pharmacology;

quadruplex; telomerase; telomere

Correspondence

Stephen Neidle, Cancer Research UK

Biomolecular Structure Group, The School

of Pharmacy, University of London,

29-39 Brunswick Square, London

WC1N 1AX, UK

Fax: +44 207 753 5970

Tel: +44 207 753 5969

E-mail: [email protected]

(Received 25 June 2009, revised 5 October

2009, accepted 6 October 2009)

doi:10.1111/j.1742-4658.2009.07463.x

The 3¢-ends of human chromosomal DNA terminate in short single￾stranded guanine-rich tandem-repeat sequences. In cancer cells, these are

associated with the telomere-maintenance enzyme telomerase together with

the end-binding protein hPOT1. Small molecules that can compete with

these proteins and induce the single-stranded DNA to form quadruplex–

ligand complexes are, in effect, able to expose these 3¢-ends, which results

in the activation of a DNA damage response and selective inhibition of cell

growth. Several of these G-quadruplex binding molecules have shown

promising anticancer activity in tumour xenograft models, which indicate

that the approach may be applicable to the treatment of a wide range of

human cancers. This minireview summarizes the available data on these

compounds and the challenges posed for drug discovery.

1118 FEBS Journal 277 (2010) 1118–1125 ª 2009 The Author Journal compilation ª 2009 FEBS