Báo cáo khoa học: Human telomeric G-quadruplex: The current status of telomeric G-quadruplexes as therapeutic targets in human cancer pdf

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Báo cáo khoa học: Human telomeric G-quadruplex: The current status of telomeric G-quadruplexes as therapeutic targets in human cancer pdf

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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: stephen.neidle@pharmacy.ac.uk (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 consequence of the end-replication effect, and once telomeric DNA is at a critically short length, cells enter p53 and Rb-dependent replicative senescence, and ultimately apoptosis. The catalytic subunit of telo- merase (hTERT in humans) has reverse transcriptase enzymatic activity and synthesizes TTAGGG repeats on to the end of the 3¢ single-stranded overhang. Inhi- bition of hTERT by siRNA, antisense or small-mole- cule inhibitors selectively inhibits cancer cell growth and strongly suggests that induction of telomere short- ening is a viable therapeutic strategy [18]. Folding the single-stranded telomeric DNA substrate of telomerase into a four-stranded quadruplex struc- ture inhibits the enzyme’s catalytic activity [19] because it ensures that the 3¢-end is inaccessible to hybridize with the telomerase RNA template, the essential first step in the catalytic cycle. The induction of quadruplex stabilization and telomerase inhibition by a quadru- plex-binding small molecule was first demonstrated using a disubstituted anthraquinone derivative [20]. Many quadruplex-binding ligands have been reported subsequently [18,21,22], although relatively few have been evaluated in cell-based assays, or even with reli- able in vitro telomerase assays [23,24]. The majority of G-quadruplex ligands contain a polycyclic heteroaro- matic core, although it is clear that this is not an essential requirement for quadruplex binding. Several effective quadruplex-binding ligands do not have this feature. The cyclic polyamine telomestatin (Fig. 1) was the first such compound [25] to show both high quad- ruplex affinity and telomerase inhibitory potency. More recent reports have demonstrated that nonconju- gated compounds that are synthetically more accessible than telomestatin can have potency against telomerase and quadruplex selectivity [26–29]. Telomeric quadruplex ligands – possible mechanisms of action The classic model of telomerase inhibition and conse- quent telomere attrition leading to senescence and apoptosis requires that cells with a mean telomere Fig. 1. Structures of quadruplex-binding ligands. S. Neidle G-quadruplexes as cancer drug targets FEBS Journal 277 (2010) 1118–1125 ª 2009 The Author Journal compilation ª 2009 FEBS 1119 length of 5 kb, a 24 h cell-doubling time and a sub- sequent loss of  100 nucleotides per round of repli- cation would reach critical telomere shortening in  40–50 days [30,31]. This was indeed the observation in dominant-negative telomerase transfection experi- ments, but would be therapeutically challenging for human cancer treatment. Initial findings using G-quad- ruplex ligands showed very different behaviour, with senescence occurring within 7–10 days after cells were first treated, and little evidence of concomitant telo- mere shortening [11,18,32]. This has subsequently been shown to be characteristic of the G-quadruplex ligand class as a whole, and the observations of on-target in vivo activity within clinically useful timescales are encouraging signs that significant single-agent clinical utility may be eventually achievable with appropriate compounds. The quadruplex-binding acridine ligands BRACO-19 and RHPS4 (Fig. 1), in common with telomestatin, induce rapid replicative senescence in cancer cells and activate the same DNA damage response that follows DNA double-strand breaks. This involves in particular ATM, p16 INK4a kinase and p53 pathways [32–35] which can be visualized by the appearance of charac- teristic DNA damage foci using an antibody to the damage response protein cH2AX [36], or by a signifi- cant population of cells undergoing end-to-end fusions in metaphase [37]. Such changes are analogous to those produced when the telomeric protein TRF2 is knocked out. This response is a consequence of the displacement of bound proteins from the single- stranded overhang, chiefly hPOT1, as well as possible uncapping of telomerase from the ends. There are likely to be multiple mechanisms involved, some of which at least have cross-talk between them (Fig. 2). For example, hPOT1 interacts with the telomeric pro- tein Tpp1 and facilitates telomere length regulation by telomerase, and hPOT1 displacement disregulates telomerase function [7,8]. Also, although the classic telomerase inhibition model does not appear to be fol- lowed by G-quadruplex-binding agents, cancer cells generally have marked telomere length heterogeneity, with some having extremely short (< 1 kb) telomeres. It has been suggested that these cells are not only sensitive to senescence, but also that their viability is critical to the cell population overall [38,39], although it is not clear to what extent telomere shortening, initially considered to be an essential marker of Fig. 2. Schematic of mechanism of action of the telomeric quadruplex ligand BRACO-19. G-quadruplexes as cancer drug targets S. Neidle 1120 FEBS Journal 277 (2010) 1118–1125 ª 2009 The Author Journal compilation ª 2009 FEBS telomerase inhibition, is relevant to the short-term effects of telomeric G-quadruplex ligands. Q-FISH studies have shown that telomestatin is localized at telomeres during replication and importantly, that telo- mere replication is unaffected in mouse embryonic fibroblast (i.e. untransformed) cell lines [40]. Validation of a telomeric quadruplex mode of action involves evidence from a number of assays. The most important are: (a) high-affinity in vitro telomeric quad- ruplex binding, with a K a value of at least 10 6 m )1 ; (b) a low level of binding to duplex DNA, with a K a value at least 10 2 less than for telomeric quadruplexes; (c) selective inhibition of cell growth, with normal human cell lines being relatively unaffected; (d) senescence; (e) inhibition of telomerase activity in cells; (f) competitive inhibition of hPOT1 binding in cells; and (g) evidence of telomere uncapping in cells from hTERT. G-quadruplex ligands as drugs In vivo activity in xenograft cancer models has been reported to date for few telomeric quadruplex ligands, notably the trisubstituted acridine compound BRACO- 19 [32], the polycyclic compound RHSP4 [34,35] and telomestatin [41] (Fig. 1). The telomeric DNA single- strand overhang is a target for all these compounds, as judged by the observations of hPOT1 and hTERT uncapping. To date, none of these molecules has pro- gressed beyond the experimental stage into clinical trial, probably in part because these compounds are insufficiently drug-like. Little data is publicly available on their ADME ⁄ pharmacokinetic properties. To date, the development of small molecules as G-quadruplex binders has been largely based on poly- cyclic planar aromatic compounds with at least one substituent terminating in a cationic group [20,21]. Normally two such substituents are required. The rationale for the planar moiety has been that this would stack effectively onto planar G-quartets, which has been confirmed by several crystallographic and NMR studies of G-quadruplex–ligand complexes [42– 47]. There is no evidence from these studies of classic intercalation between G-quartets and all analyses con- cur in finding that ligands stack onto a terminal G-quartet of a quadruplex. Substituents are normally short acyclic chains, such as -(CH 2 ) 3 - with a terminal cationic nitrogen-containing group such as diethyl- amine, pyrrolidine or piperidine. Structure-based drug discovery does have these few structures as starting points [42–47], although these also indicate that the flexibility of the TTA loops is ligand dependent, and therefore structural information for a given class of ligand would be highly desirable. Also, there are no experimental structural data as yet on folded telomeric DNA sequences containing eight or twelve TTAGGG repeats (i.e. with two or three consecutive quadruplexes), which may be more representative of the totality of the single-stranded overhang, and which may be important for these ligands being able to differentiate telomeric quadruplexes from others in the genome. It has long been realized that therapeutically effec- tive quadruplex-binding ligands should have minimal duplex DNA affinity (and therefore more generalized toxicity), and assays for duplex:quadruplex selectivity are routinely performed in many laboratories. The structural requirements for selectivity have not yet been fully clarified, but mostly involve those steric fea- tures that are incompatible with the dimensions of a double helix. A large number of genomic DNA and RNA G-quadruplexes may also be drug targets [48– 53], many of which are involved in proliferation. It is plausible that G-quadruplex-binding molecules even with relatively modest selectivity between various G-quadruplexes, may still have utility in cancer therapeutics, provided they have low toxicity to normal cells. Of greater practical importance is that future G-quadruplex ligands are developed with regard to their ability to be used as drugs, so that they have: (a) effective and selective tumour uptake and penetra- tion, (b) acceptable pharmacokinetic characteristics and metabolism, and (c) a significant therapeutic window. The features common to most current quadruplex ligands, of several cationic charges and large hydro- phobic surface area, do aid cellular uptake (probably by active transport mechanisms), but may also enable a high background of nonspecific binding to cellular components, and are not consistent with oral bio-avail- ability (although this in itself may not be an important goal). The three positive charges on the BRACO-19 molecule are probably a factor in the inability of this compound to penetrate larger tumours in both the UXF1138L and A431 xenograft models [32,54] (Table 1). Compound AS1410 was devised [55] to have increased hydrophobicity compared with its parent compound BRACO-19 as a result of modifications to the substituents at the 9-position. This resulted in an increase in plasma half-life from 1 to 2 h. The limited in vivo data available (Table 1) suggest that telomeric quadruplex ligands may be useful for the treatment of solid tumours; to date there is very little data on haematological cancers. Notable findings include that of single-agent activity for RHSP4 in a metastatic melanoma model, as well as in a melanoma line resistant to the platinum drug DDP [56]. RHPS4 S. Neidle G-quadruplexes as cancer drug targets FEBS Journal 277 (2010) 1118–1125 ª 2009 The Author Journal compilation ª 2009 FEBS 1121 appears able to penetrate significant tumour masses (Table 1), in accord with its single net positive charge combined with the relatively small size of this mole- cule. Data on two other quadruplex-binding ligands have also been included. The porphyrin compound TMPyP4, which does bind with high affinity to a wide range of quadruplex nucleic acids, albeit with low selectivity, has been reported to show anticancer activ- ity in MX-1 mammary tumours and PC-3 human pros- tate carcinomas [57]. Although quadruplexes in the promoter region of the c-myc oncogene have been suggested as a target for this compound, it is also an established telomerase inhibitor, so action at the telomere level should not be ruled out. In vivo data on the recently described quadruplex-binding fluoroquino- lone derivative Quarfloxin (CX-3543) is included. It is currently in clinical trials so its pharmacological profile has relevance to other quadruplex ligands. This agent was initially suggested to be targeting a c-myc pro- moter quadruplex, but is now believed to function by selectively disrupting nucleolin ⁄ rDNA quadruplex complexes [58]. It does not show the cellular behaviour characteristic of a telomere targeting agent. It is encouraging for future clinical applications that several G-quadruplex ligands show in vivo synergistic activity (Table 2) with conventional cytotoxic agents, such as cis-platinum, taxol and camptothecin deriva- Table 1. Selected in vivo data on quadruplex-binding ligands. Tumour responses have been estimated from survival curves and other avail- able data. Single-agent studies. i.p., intraperitoneal; i.v., intravenous. G4 ligand Xenograft model Mean initial tumour size Dosage (mgÆkg )1 ) Tumour response Days to complete response Ref TMPyP4 MX-1 mammary tumor 100 mg a 10, 20; i.p. Survival increase from 45% to 75% 60 57 TMPyP4 PC-3 human prostate carcinoma 60 mg 40; i.p. 60% tumour shrinkage 18 57 Telomestatin U937 human lymphoma 1395 mm 3 15 80% tumour shrinkage 21 41 BRACO-19 UXF1138L human uterine carcinoma 68 mm 3 2; i.p. 96% tumour shrinkage + some complete remissions 28 32 BRACO-19 A431 human epithelial carcinoma 1080 mm 3 2; i.p. Not significant – 54 Quarfloxin MDA-MB-231 human breast cancer > 125 mm 3 6.25, 15.5; i.v. 50% tumour shrinkage 37 58 Quarfloxin MIA PaCa-2 human pancreatic cancer > 125 mm 3 5; i.v. 59% tumour shrinkage 35 58 RHPS4 UXF1138L human uterine carcinoma 5 · 5 mm 5; oral 30% tumour shrinkage 28 33 RHPS4 M14, LP, LM melanoma 300–350 mg 10; i.p. 40–51% tumour weight reduction 15 56 RHPS4 b CG5 breast carcinoma 300 mg 15; i.v. 75% tumour shrinkage 30 35 a Animals were initially treated with cyclophosphamide to minimize tumour burden. b RHPS4 was reported to have an antitumour effect in a number of other tumour types in this study. Table 2. In vivo studies of quadruplex-binding ligands in combination with established anticancer drugs. Tumour responses have been estimated from survival curves and other available data. Studies in combination with established anticancer drugs. G4 ligand Xenograft model Initial tumour size Dosage (mgÆkg )1 ) Drug 2 Tumour response Ref BRACO-19 A431 epidermal carcinoma 1080 mm 3 2 Paclitaxel 68% tumour shrinkage 54 AS1410 A549 lung carcinoma 10 mm 3 1 Cis-platinum  75% tumour shrinkage 59 RHPS4 UXF1138L human uterine carcinoma 5 · 5 mm 5 Taxol Complete remissions 33 RHPS4 a HCT116, HT29 colorectal carcinomas 300–350 mg 10 Irinotecan 80% tumour weight reduction 56 a A number of other combinations, with a range of anticancer drugs, were also reported in this study. G-quadruplexes as cancer drug targets S. Neidle 1122 FEBS Journal 277 (2010) 1118–1125 ª 2009 The Author Journal compilation ª 2009 FEBS tives [33,54,56,59], although the detailed mechanism of this effect remains to be established. The order in which the drugs are administered appears to be an important determinant of whether a particular combi- nation is synergistic or antagonistic. 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