TELOMERASE-INHIBITION AS ANTI-CANCER THERAPY: CURRENT ADVANCES & FUTURE PERSPECTIVE (original) (raw)

A highly selective telomerase inhibitor limiting human cancer cell proliferation

The EMBO Journal, 2001

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo ef®cacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These ®ndings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities.

Telomeres and Telomerase: Pharmacological Targets for New Anticancer Strategies?

Current Cancer Drug Targets, 2006

Telomeres are located at the ends of eukaryotic chromosomes. Human telomerase, a cellular reverse transcriptase, is a ribonucleoprotein enzyme that catalyzes the synthesis and extension of telomeric DNA. It is composed of at least, a template RNA component (hTR; human Telomerase RNA) and a catalytic subunit, the telomerase reverse transcriptase (hTERT). The absence of telomerase is associated with telomere shortening and aging of somatic cells, while high telomerase activity is observed in over 85% of human cancer cells, strongly indicating its key role during tumorigenesis. Several details regarding telomere structure and telomerase regulation have already been elucidated, providing new targets for therapeutic exploitation. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase is endowed of additional functions in the control of growth and survival of tumor cells that do not depend only on the ability of this enzyme to maintain telomere length. This observation suggests that inhibiting telomerase or its synthesis may have additional anti-proliferative and apoptosis inducing effect, independently of the reduction of telomere length during cell divisions. This article reviews the basic information about the biology of telomeres and telomerase and attempts to present various approaches that are currently under investigation to inhibit its expression and its activity. We summarize herein distinct anti-telomerase approaches like antisense strategies, reverse transcriptase inhibitors, and G-quadruplex interacting agents, and also review molecules targeting hTERT expression, such as retinoids and evaluate them for their therapeutic potential.

Telomerase Inhibitors from Natural Products and Their Anticancer Potential

International journal of molecular sciences, 2017

Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy-a hallmark of cancer-and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transc...

Therapeutic Anticancer Approaches Targeting Telomerase and Telomeres

Multi-Targeted Approach to Treatment of Cancer, 2014

Telomeres and telomerase are attractive targets for anticancer therapy. This is evidenced with the facts that majority of human cancers express the enzyme telomerase which is utmost important to maintain the telomere length, thereby to ensure indefinite cell proliferation -a hallmark of cancer. In human cells, a structure referred to as telomere has been identified to cap the terminal regions of chromosomes which can protect the ends of DNA strands from degradation and fusion, whereas telomerase plays a pivotal role in cellular immortality and tumorigenesis. Henceforth, strategies have been made to induce telomerase inhibition target virtually all of the major components of ribonucleoprotein holoenzyme and related cell signal pathways that regulates its activity which includes telomerase reverse transcriptase (hTERT) catalytic subunit, the telomere RNA component (hTERC), and associated proteins. It is noteworthy here that most of the cancers have an alternative lengthening of telomere termed as ALT even in the absence of telomerase activity. In these cases, there is an urgent need to understand the cell signaling pathways for ALT mechanism which can be used as therapeutic targets. Other strategies have been developed to target the protein associated with telomerase at the telomeric ends of chromosomes such as tankyrase. Increasing evidences suggest that directly targeting telomeric DNA using agents directed against the shelterin complex may also have anticancer activity. The limitations of strategies remain to be resolved to facilitate the clinical applications. In this chapter, recent development of strategies against these targets shall be discussed.

Telomere maintenance mechanisms as a target for drug development

Oncogene, 2000

The shortening of the telomeric DNA sequences at the ends of chromosomes is thought to play a critical role in regulating the lifespan of human cells. Since all dividing cells are subject to the loss of telomeric sequences, cells with long proliferative lifespans need mechanisms to maintain telomere integrity. It appears that the activation of the enzyme telomerase is the major mechanism by which these cells maintain their telomeres. The proposal that a critical step in the process of the malignant transformation of cells is the upregulation of expression of telomerase has made this enzyme a potentially useful prognostic and diagnostic marker for cancer, as well as a new target for therapeutic intervention for the treatment of patients with cancer. It is now clear that simply inhibiting telomerase may not result in the anticancer eects that were originally hypothesized. While telomerase may not be the universal target for cancer therapy, we certainly believe that targeting the telomere maintenance mechanisms will be important in future research aimed toward a successful strategy for curing cancer.

Targeting human telomerase for cancer therapeutics

Cytotechnology, 2004

The enzyme telomerase is involved in the replication of telomeres, specialized structures that cap and protect the ends of chromosomes. Its activity is required for maintenance of telomeres and for unlimited lifespan, a hallmark of cancer cells. Telomerase is overexpressed in the vast majority of human cancer cells and therefore represents an attractive target for therapy. Several approaches have been developed to inhibit this enzyme through the targeting of its RNA or catalytic components as well as its DNA substrate, the single-stranded 3¢-telomeric overhang. Telomerase inhibitors are chemically diverse and include modified oligonucleotides as well as small diffusable molecules, both natural and synthetic. This review presents an update of recent investigations pertaining to these agents and discusses their biological properties in the context of the initial paradigm that the exposure of cancer cells to these agents should lead to progressive telomere shortening followed by a delayed growth arrest response.

Preclinical and clinical strategies for development of telomerase and telomere inhibitors

Annals of Oncology, 1997

Background: Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anticancer strategy. Design: In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.

Telomerase inhibition as cancer therapy

Cancer letters, 2003

A number of different approaches have been developed to inhibit telomerase activity in human cancer cells. Different components and types of inhibitors targeting various regulatory levels have been regarded as useful for telomerase inhibition. Most methods, however, rely on successive telomere shortening. This process is very slow and causes a long time lag between the onset of inhibition and the occurrence of senescence or apoptosis as a reversal of the immortal phenotype. Many telomerase inhibitors seem to be most efficient when combined with conventional chemotherapeutics. There are some promising approaches that seem to circumvent the slow way of telomere shortening and induce fast apoptosis in treated tumor cells. It has been demonstrated that telomerase may be involved in triggering apoptosis, but the underlying molecular mechanism remains unclear. q

Therapeutic Targets in Telomerase and Telomere Biology of Cancers

Indian Journal of Clinical Biochemistry, 2020

Telomeres play an important role to conserve genomic integrity by protecting the ends of chromosomes in normal cells. Since, their progressive shortening during successive cell division which lead to chromosomal instability. Notably, telomere length is perpetuated by telomerase in large majority of cancers, thereby ensure indefinite cell proliferation-a hallmark of cancer-and this unique feature has provided telomerase as the preferred target for drug development in cancer therapeutics. Cancer cells have acquired the potential to have telomere length maintenance by telomerase activation-up-regulation of hTERT gene expression in tumor cells is synchronized by multiple genetic and epigenetic modification mechanisms viz hTERT structural variants, hTERT promoter mutation and epigenetic modifications through hTERT promoter methylation which have been implicated in various cancers initiation and progression. In view of these facts, strategies have been made to target the underlining molecular mechanisms involved in telomerase reactivation as well as of telomere structure with special reference to distortion of sheltrin proteins. This review is focussed on extensive understanding of telomere and telomerase biology. which will provide indispensable informations for enhancing the efficiency of rational anticancer drug design. However, there is also an urgent need for better understanding of cell signalling pathways for alternative lengthening of telomere which is present in telomerase negative cancer for therapeutic targets.

Natural and pharmacological regulation of telomerase

Nucleic Acids Research, 2002

The extremities of eukaryotic chromosomes are called telomeres. They have a structure unlike the bulk of the chromosome, which allows the cell DNA repair machinery to distinguish them from 'broken' DNA ends. But these specialised structures present a problem when it comes to replicating the DNA. Indeed, telomeric DNA progressively erodes with each round of cell division in cells that do not express telomerase, a specialised reverse transcriptase necessary to fully duplicate the telomeric DNA. Telomerase is expressed in tumour cells but not in most somatic cells and thus telomeres and telomerase may be proposed as attractive targets for the discovery of new anticancer agents.