Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells, proliferation potential is strictly limited and senescence follows approximately 50–70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. Undoubtedly, DNA polymerase is not capable of completely copying DNA at the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during each cell cycle, which results in gradual telomere length shortening. Critically short telomeres cause senescence, following crisis and cell death. However, in tumor cells the system of telomere length maintenance is activated. Much work has been done regarding the complex telomere/telomerase as a unique target, highly specific in cancer cells. Telomeres have additional proteins that regulate the binding of telomerase. Telomerase, also associates with a number of proteins forming the sheltering complex having a central role in telomerase activity. This review focuses on the structure and function of the telomere/telomerase complex and its altered behavior leading to disease, mainly cancer. Although telomerase therapeutics are not approved yet for clinical use, we can assume that based on the promising in vitro and in vivo results and successful clinical trials, it can be predicted that telomerase therapeutics will be utilized soon in the combat against malignancies and degenerative diseases. The active search for modulators is justified, because the telomere/telomerase system is an extremely promising target offering possibilities to decrease or increase the viability of the cell for therapeutic purposes.
Drug repositioning refers to the concept of discovering novel clinical benefits of drugs that are already known for use treating other diseases. The advantages of this are that several important drug characteristics are already established (including efficacy, pharmacokinetics, pharmacodynamics and toxicity), making the process of research for a putative drug quicker and less costly. Drug repositioning in oncology has received extensive focus. The present review summarizes the most prominent examples of drug repositioning for the treatment of cancer, taking into consideration their primary use, proposed anticancer mechanisms and current development status.
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.
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.
Telomeropathies involve a wide variety of infrequent genetic diseases caused by mutations in the telomerase maintenance mechanism or the DNA damage response (DDR) system. They are considered a family of rare diseases that often share causes, molecular mechanisms and symptoms. Generally, these diseases are not diagnosed until the symptoms are advanced, diminishing the survival time of patients. Although several related syndromes may still be unrecognized this work describes those that are known, highlighting that because they are rare diseases, physicians should be trained in their early diagnosis. The etiology and diagnosis are discussed for each telomeropathy and the treatments when available, along with a new classification of this group of diseases. Ethical and legal issues related to this group of diseases are also considered.
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