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Telomerase as a Cancer Target. Development of New Molecules

View Article: PubMed Central - PubMed

ABSTRACT

Telomeres are the terminal part of the chromosome containing a long repetitive and non-codifying sequence that has as function protecting the chromosomes. In normal cells, telomeres lost part of such repetitive sequence in each mitosis, until telomeres reach a critical point, triggering at that time senescence and cell death. However, in most of tumor cells in each cell division a part of the telomere is lost, however the appearance of an enzyme called telomerase synthetize the segment that just has been lost, therefore conferring to tumor cells the immortality hallmark. Telomerase is significantly overexpressed in 80–95% of all malignant tumors, being present at low levels in few normal cells, mostly stem cells. Due to these characteristics, telomerase has become an attractive target for new and more effective anticancer agents. The capability of inhibiting telomerase in tumor cells should lead to telomere shortening, senescence and apoptosis. In this work, we analyze the different strategies for telomerase inhibition, either in development, preclinical or clinical stages taking into account their strong points and their caveats. We covered strategies such as nucleosides analogs, oligonucleotides, small molecule inhibitors, G-quadruplex stabilizers, immunotherapy, gene therapy, molecules that affect the telomere/telomerase associated proteins, agents from microbial sources, among others, providing a balanced evaluation of the status of the inhibitors of this powerful target together with an analysis of the challenges ahead.

No MeSH data available.


Schematic representation of telomerase and its associated proteins.
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Figure 1: Schematic representation of telomerase and its associated proteins.

Mentions: In most mammals, the maintenance of telomeric length is carried out mainly by telomerase. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT and an RNA component [hTR] which acts as a template for the addition of a short repetitive sequence [dTTAGGG]n in the 3′ end of the telomeric DNA and species-specific accessory proteins. These accessory proteins regulate telomerase biogenesis, subcellular localization and function in vivo. For instance, analysis of affinity-purified telomerase from HeLa cells has identified integral protein components of human telomerase: dyskerin, NHP2; NOP10, pontin/reptin, Gar1 and TCAB1 [22] Fig. (1). As described the complex telomere/telomerase is integrated by numerous molecules with different functions elegantly reviewed by Rubtsova et al [23].


Telomerase as a Cancer Target. Development of New Molecules
Schematic representation of telomerase and its associated proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997958&req=5

Figure 1: Schematic representation of telomerase and its associated proteins.
Mentions: In most mammals, the maintenance of telomeric length is carried out mainly by telomerase. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT and an RNA component [hTR] which acts as a template for the addition of a short repetitive sequence [dTTAGGG]n in the 3′ end of the telomeric DNA and species-specific accessory proteins. These accessory proteins regulate telomerase biogenesis, subcellular localization and function in vivo. For instance, analysis of affinity-purified telomerase from HeLa cells has identified integral protein components of human telomerase: dyskerin, NHP2; NOP10, pontin/reptin, Gar1 and TCAB1 [22] Fig. (1). As described the complex telomere/telomerase is integrated by numerous molecules with different functions elegantly reviewed by Rubtsova et al [23].

View Article: PubMed Central - PubMed

ABSTRACT

Telomeres are the terminal part of the chromosome containing a long repetitive and non-codifying sequence that has as function protecting the chromosomes. In normal cells, telomeres lost part of such repetitive sequence in each mitosis, until telomeres reach a critical point, triggering at that time senescence and cell death. However, in most of tumor cells in each cell division a part of the telomere is lost, however the appearance of an enzyme called telomerase synthetize the segment that just has been lost, therefore conferring to tumor cells the immortality hallmark. Telomerase is significantly overexpressed in 80–95% of all malignant tumors, being present at low levels in few normal cells, mostly stem cells. Due to these characteristics, telomerase has become an attractive target for new and more effective anticancer agents. The capability of inhibiting telomerase in tumor cells should lead to telomere shortening, senescence and apoptosis. In this work, we analyze the different strategies for telomerase inhibition, either in development, preclinical or clinical stages taking into account their strong points and their caveats. We covered strategies such as nucleosides analogs, oligonucleotides, small molecule inhibitors, G-quadruplex stabilizers, immunotherapy, gene therapy, molecules that affect the telomere/telomerase associated proteins, agents from microbial sources, among others, providing a balanced evaluation of the status of the inhibitors of this powerful target together with an analysis of the challenges ahead.

No MeSH data available.