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Introduction
Telomeres are specialized
protein-DNA structures at the end of eukaryotic chromosomes. They
protect chromosomes from end-to-end fusion and nuclease degradation.
In humans, telomeres consists of approximately 4-14 kb of TTAGGG
duplex repeats and 150-200 bases of single-stranded DNA overhang
running 5' to 3' toward the end of chromosome[1]. Because
of the end replication problem[2,3], telomeres in human
cells erode by approximately 100 bp with each cell division[4].
Telomerase is the key enzyme for the stabilization of telomere by
adding TTAGGG repeats to telomere ends[5]. It is a
ribonucleoprotein that utilizes its RNA component as the template to
synthesis telomere repeats. In humans, telomerase activity is not
detected in most somatic cells[6,7]. Progressive telomere
shortening after each cell division leads to cellular senescence
after 60-80 population doublings[4]. Escaping senescence
leads to further shortening of telomeres and can eventually cause
cells to enter crisis and cell death[8]. Cells at this
stage appear aneuploidy because telomere loss induces chromosome
instability through the breakage/fusion/bridge cycles[9].
Few cells stabilize telomere length through activating telomerase
activity[10]. Indeed, telomerase activity is detected in
approximately 90% to 95% of human immortal cell lines and up to 85%
of can-cers[6,7]. In the remaining 5% to 10% immortal
cells, telomerase-independent telomere maintenance mechanism, also
known as the alternative lengthening of telomeres (ALT), were used
to maintain telomere length[11]. These cells could then
divide with great capacity.
Because telomerase is an essential
component for the proliferation of cancer cells, targeting telomere
and telomer-ase has drawn the interests of scientists in anti-cancer
and regeneration drug development. In the present study, we discuss
various approaches used including the small molecules that have been
developed using telomere and telomerase as targets for
chemotherapeutic developments.
Inhibition of telomerase activity
Although tumors are caused by
mutations that activate oncogenes and repress tumor suppressor
genes, they still need to overcome telomere-dependent senescence for
their indefinite divisions. Because telomerase activity is crucial
for supporting indefinite proliferation of most tumor cells,
selective inhibition of telomerase activity only limits the
proliferation capacity of tumor cells[12]. In principle,
a telomerase-specific inhibitor is expected to affect telomere
maintenance. It has been proposed that a telomerase inhibitor can be
utilized as complementary therapy in cancer chemotherapeutics[12,13].
However, more and more studies indicate that telomerase also plays
an important role in the telomere-capping function[14].
Inhibition of telomerase can affect the survival of cancer cells.
Indeed, several published reports have found that the inhibition of
telomerase can cause apoptosis without long-term treatment of the
cells[15-17]. Thus, it is expected that the inhibition of
telomerase activity in cells produces different effects depending on
the means of inhibition. Because telomerase activities are also
presented in human germline cells, stem cells, peripheral blood
mononuclear cells, and normal fibroblasts[6,18,19], it is
likely that telomerase inhibition also affects these cells. The
potential risks of telomerase inhibition have to be carefully
evaluated in these cells.
Targeting telomerase
Telomerase is a unique reverse transcriptase consisting of two major
components, the RNA template (hTR) and the catalytic subunit
(hTERT). Both components have been used as targets for telomerase
inhibition. The first successful case was reported in 1995 where
anti-sense RNA against the first 185 nucleotides of the hTR
molecule was introduced into HeLa cells and caused progressive
telomere shortening and eventually cell crisis[20].
Similarly, short peptide nucleic acid (PNA) or 2'-O-methyl-RNA
(2'-O-meRNA) oligomers with enhanced binding properties to
hTR efficiently inhibit telomerase activity, and lead to
progressive telomere shortening in immortal breast epithelial cells[21].
Synthetic oligonucleotides applying 2-5A (5'-phosphorylated
2'-5'-linked oligoadenylate)-linked antisense approaches were used
to degrade hTR and caused apoptosis in several cancer models
including glioma[15]. Utilizing ribo-zymes to cleave
hTR has also been reported in several published studies[13,22].
These small catalytically-active RNA molecules cleave their RNA
substrate in a sequence-dependent manner. Interestingly, the
inhibition of telomerase activity using hammerhead ribozyme against
hTR appears to sensitize the breast epithelial cells to
topoisomerase inhibitors[13]. Another approach is to
target the catalytic subunit of telomerase hTERT. A dominant
negative mutant of hTERT was identified that caused complete
inhibition of telomerase activity, telomere shortening, and
increased cell apoptosis when introduced into cancer cells[16,17].
This dominant negative-hTERT also reduced tumorigenicity in nude
mice[16].
Even though antisense, ribozyme, and
dominant negative approaches showed promising results in inhibiting
telomerase activity, these approaches were less applicable because
the techniques for effective and convenient delivery of RNA or
proteins were not available for clinical settings. Thus, small
molecule compounds that inhibit telomerase activity appear to be
more suited. There were several types of compounds identified,
including nucleotide analogs that inhibit the catalytic activity of
the enzyme and non-nucleotide analogs that have inhibitory effects
less characterized. As these molecules have been extensively
reviewed recently[23,24], they will not be discussed
further here. However, it is worthy of noting that compound BIBR1532
was shown to inhibit telomerase non-competitively[25] and
cause telomere shortening and senescence in cancer cells[26].
Moreover, cancer cells pretreated with BIBR1532 showed a reduced
tumorigenic potential in the mouse xenograft model[26].
With the IC50 value at nanomolar concentration, BIBR1532
and several other compounds should have the potential for further
developments[26-28].
Targeting telomeres In
humans, the G-rich telomeric DNA tails are capable of forming a
planar structure, termed G-quadruplexes, through non-Watson-Crick
Hoogsteen hydrogen bonding in vitro[29]. A recent
study has detected the G-quadruplex-induced fluorescence in
telomeres of meta-phase chromosomes using a G-quadruplex-selective
fluorescent compound BMVC [3,6-bis(1-methyl-4-vinylpyridinium)
carbazole diiodide], providing the first evidence for the presence
of G-quadruplexes inside human cells[30]. In addition to
telomeres, the G-quadruplex structure was also reported in the
transcriptional regulatory region of several important oncogenes
that their expression could be regulated by them[31].
Thus, even though telomeres in human cells were shown to form
T-looped structures[32], it appears that human telomeres
could also form G-quadruplex structures inside cells. The function
of G-quadruplex structure in telomeres is not clear. However,
because G-quadruplexes formed by telomeric DNA sequences were not
the substrates for telomerase[33], the G-quadruplex
structure might have a role in telomere maintenance and
transcriptional regulation of oncogene expression. Agents that
stimulate the formation or stabilize G-quadruplexes become important
targets for drug design.
Several researchers have adopted a
structure-based design and synthesis approach to identify lead
compounds that interact with G-quadruplexes[24].
Successful lead compounds that were identified include derivatives
of proflavins[28], porphyrins[34], acridines[35],
anthraquinones[36], triazines[37], and
carbazoles[27]. All of these identified compounds have
planar aromatic rings. Molecular modeling studies have indicated
that these planar structures bind to the G-quadruplexes through a
series of interactions to the planar and loop structures of
G-quadruplexes[28,38,39]. These interactions stabilize
the structure of G-quadruplexes and increase the melting temperature
upon binding. For example, a carbazole derivative BMVC increases the
melting temperature (Tm) of G-quadruplexes formed by human telomeric
DNA by as much as 13 ºC[40]. It is interesting to note
that these planar compounds appear to be very effective in affecting
telomerase as several of these compounds have the IC50 at
the range of nanomolar concentration[27,28,37].
Modulation of telomerase
expression
Direct inhibition of telomerase at
the activity level provides a simpler mean to target telomerase for
cancer therapy. In recent years, several reports have also attempted
to target the expression of telomerase at the gene level. Repression
of telomerase expression in cancer cells would have applications in
anti-cancer chemotherapies whereas activation of telomerase
expression in normal cells would have applications in regeneration
therapies.
Repressing hTERT expression in
cancer cells In human cells, the expressing of telomerase
catalytic enzyme hTERT correlates well with the telomerase activity[41].
It also appears that regulation at the transcriptional level was the
most important step for hTERT expression[42] even though
regulation at the splicing[43,44], post-translational
modification[45-48], or subcellular localization[49]
were also reported. Thus, targeting hTERT transcription is the focus
for developing agents that repress hTERT expression. However, there
were only a limited number of reports targeting hTERT expression.
Retinoic acid represents the most characterized small molecule in
this category. Retinoic acid at the micromolar concentration
down-regulates telomerase activity in human leukemia cells[50,51].
Long-term treatment of leukemia cells with retinoic acid leads to
telomere shortening and eventually cell death[50]. The
specificity of retinoic acid is a concern in future drug
development. An ideal compound should only affect the expression of
the hTERT gene. Nevertheless, repressing hTERT expression is an
effective way to limit the proliferation capacity of cancer cells.
Recently, a cell-based system was developed that enables the
screening of small molecule compounds for repressing hTERT
expression[52]. The hTERT promoter was ligated downstream
to a reporter gene, GFP or SEAP (secreted alkaline phosphatase), and
introduced into human cancer cells. The expression of hTERT could
then be monitored by the reporter genes. A series of anthraquinone
derivatives were tested for their ability to repress hTERT
expression using this cell-based system[52]. Even though
anthraquinone derivatives did not repress hTERT expression, it is
anticipated that small molecule compounds that repress hTERT
expression could be screened and identified using this approach.
Activating hTERT expression in
normal cells While telomerase inhibition or hTERT repression
could have applications in anticancer therapeutics, telomerase
activation could serve as a mean to extend the lifespan of normal
cells and to treat degenerative diseases. For example, liver
cirrhotic pathology is caused by continual hepatocyte destruction
over many years. The end-stage of cirrhosis is characterized by
extensive fibrotic replacement and cessation of hepatocyte
proliferation. In a mouse experimental liver cirrhosis model, the
pathology is alleviated through activation of telomerase activity[53].
Also in Werner syndrome cells, the accelerated aging phenotype is
reversed by telomerase activation[54]. Moreover, the life
span of human bone marrow stromal stem cells are achieved by
telomerase expression[55,56]. These ex vivo
expanded stem cells could have profound applications in, for
instance, tissue engineering.
Ectopically expressed hTERT by
introducing a virus promoter-driven hTERT gene into normal human
cells has been found to be very effective in increasing hTERT mRNA
expression and telomerase activity, and extending the life span of
normal cells[10,57]. For example, the replication
capacity of skin fibroblasts[10] and adult mesenchymal
stem cells[58] could be expanded with the introduction of
a viral promoter driven hTERT gene. However, given the role of
telomerase in cancer and the introduced DNA which integrates
randomly into chromosomes, this type of approach might cause some
risks. Although some reports indicated that ectopic expression of
telomerase did not cause transformation phenotypes or
cancer-associated changes[59,60], more and more studies
raise concerns about the future application of cells immortalized by
ectopic hTERT expression in normal cells. Telo-merase overexpression
in mice has been found to increase epidermal tumors and promote
mammary carcinomas[58,61,62] and that expressing hTERT in
human mesenchymal stem cells renders these cells tumorigenic[58].
Thus, the ideal situation would be controlled expression of hTERT in
target cells to avoid unnecessary side-effects. One approach is
using small molecules that activate telomerase upon addition and
return to the repressed state upon removal which might provide the
solution for controlled expression of hTERT. This approach also
avoids the uncertainty concerning the integration of DNA into
chromosomes.
There are several molecules which
have been identified that affect hTERT expression through inhibiting
DNA methylation or histone deacetylation. Normal human fibroblast
treated with 5-azacytidine (5-AZC) can cause demethylation of the
CpG islands within hTERT promoter. It then turns on hTERT mRNA
expression and activates telomerase acti-vity[63,64].
Similarly, histone deacetylase inhibitor tricostain A (TSA) causes
activation of hTERT mRNA expression and telomerase activity in human
normal cells[65,66]. However, because both DNA
methylation and histone deacetylation are general mechanisms in
controlling gene expression in human cells, the treatment of 5-AZC
or TSA would have broad effects on cellular gene expressions. To
achieve selective activation of hTERT expression, a more specific
promoter-targeted agent is desired. Sequence analysis of hTERT
promoter reveals an estrogen response element (ERE) located upstream
to the transcription start site. The function of ERE is established
in normal human ovary epithelium cells where the addition of
17â-estradiol activates the expression of hTERT and telomerase
activity[67]. Thus, telomerase activity could be
activated by estrogen in cells with estrogen receptors. However,
since estrogens also activate the telo-merase activities in cancer
cells with estrogen receptor [67-69], the applicability
of estrogen or its analogs in clinics remains to be evaluated.
Similar to the approach used in identifying small molecule
compounds, a cell-based reporter system was developed in normal
human cells that enabled the identification of several bis-substituted
derivatives of anthraquinones that activate hTERT[52].
Unlike inhibitors of DNA methylation or histone deacetylation, the
repression of hTERT expression by these anthraquinones appears to be
specific as they do not activate the expression of reporter gene
driven by a virus promoter. Using a similar cell-based chemical
screening strategy, compound CGK1026 was also identified to activate
hTERT expression in normal human fibroblasts[70]. CGK1026
activates hTERT expression by affecting the interaction between
E2F-pocket protein and histone deacetylase. The effect of CGK1026 on
other promoters is still unclear.
Telomerase-directed tumor gene
therapy
One of the major goals in anticancer
therapies is to target toxic agents to tumor cells specifically to
minimize the effects toward normal cells. The specific expression of
telomerase hTERT in most types of tumors provides a good
discrimination between cancer and normal cells[6,7].
Deletion analysis of the hTERT promoter reveals a core promoter
region located approximately 200 bp upstream of the transcription
start site, and is sufficient to confer its specific expression in
cancer cells[71]. The property of hTERT promoter has been
applied to restrict the expression of therapeutic genes in tumors.
The therapeutic genes utilized include apoptosis-inducing[72-74],
toxin-encoding[75], chemotherapeutic sensitizer[71],
xenoantigen[76] genes, or genes used in gene-directed
enzyme prodrug therapy (GDEPT)[77,78]. These hTERT
promoter-driven therapeutic genes were introduced into tumor cells
through liposome- or virus-mediated pathways. As expected from the
expression pattern of telomerase, this type of approach selectively
kills virtually all types of telomerase-positive cancer cells
without affecting the viability of telomerase-negative cells in both
cellular and animal xenograft models. Thus, hTERT directed tumor
gene therapy appears to be a promising approach in treating
telomerase-positive tumors. Because hTERT expression varies in
different telomerase-positive cells[72-74], it is
anticipated that telomerase-directed tumor gene therapy would work
better in cancer cells with high levels of hTERT expression.
Summary
Because of the unique property of
telomere and telomerase in cancer and the aging process, they have
been the targets for new drug developments toward anticancer or
regenerative disease therapeutics. In addition to various approaches
that have been described here, other approaches based on the
property of telomerase have also been reported. For example, hTERT
has been reported as a tumor-associated antigen in a wide range of
tumors. These hTERT-derived tumor antigens could be recognized by
cytotoxic T lymphocytes that could then be applied in designing
anticancer immunotherapeutic strategies[79,80]. It is
anticipated that other novel approaches based on telomere functions
will be developed.
Acknowledgement
We thank Yu-ling LEE for reading the
manuscript.
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