Telomerase activity, cell proliferation, and cancer pnas. The differential expression of the telomerase enzyme in normal and cancer cells have led to the evolution of tumour specific anti telomerase approaches which inhibit the telomerase enzyme activity so as to destabilise and shorten the telomeres leading to senescence in cancer cells. Imagine a car with an accelerator stuck to the floorboard. Highly selective smail molecule inhibitors will be needed to understand the biological basis for this observation and to determine if. Telomeres, telomerase and cancer reprint an unusual enzyme called telomerase acts on parts of chromosomes known as telomeres.
Measuring telomerase may be a new way to detect cancer. Cancer cells have plenty of telomerase, which allows them to live and grow much longer than normal cells in our body, chen said. The chapters in this volume have been written by leading experts from the field. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with. Telomerase is overexpressed in many advanced cancers, but assessing its potential as a therapeutic target requires us to understand what it does and how it does it, said senior author ronald depinho, m. This has implications for thinking about telomerase as a serious anti ageing intervention. Based on the telomere hypothesis, anti telomerase inhibitors should selectively interfere with telomere maintenance in telomerase positive cancer cells. Other scientists, however, point out that mice lacking telomerase are a poor standin for the normal. Besides cancer, short telomeres are thought to cause other diseases that we associate with aging, such as osteoarthritis, diabetes, and cardiovascular disease. Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a speciesdependent telomere repeat sequence to the 3 end of telomeres. Cancer, antiaging therapy may benefit from discovery made.
Telomerase inhibitors from natural products and their. The discovery of telomerase at uc berkeley more than 30 years ago triggered enormous interest in the role the enzyme plays in aging and cancer and sparked efforts to. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to metastasize to distant organs. Nevertheless, some cancer cells do not express telomerase. The main function of htert is a reverse transcriptase activity that adds a sixbase dna repeat onto chromosome ends and prevents their shortening during. Another occurs when telomeres are so short that massive endfusion events prevent further replication. The main function of htert is a reverse transcriptase activity that adds a sixbase dna repeat onto chromosome ends and prevents their shortening during successive. Telomerase gene antitherapy stalls tumors growing in. Telomeres and telomerase in aging, disease, and cancer.
Besides that, the development of telomerase inhibitors as anticancer agents is reasonable and. The knowledge derived from preclinical studies reveals a complex scenario in which low magnesium has both anti and protumour effects, such as inhibition of tumour growth at its primary site and facilitation of tumour implantation at its metastatic sites. The enzyme has recently been found in many human tumors and is being. The available data indicate that alt involves homologous recombinationmediated dna replication and requires the activity of the mre11rad50nbs1 recombination complex. Some researchers are trying to do this by destroying the telomerase in cancer cells.
The downside is that telomerase is often mutated in human cancers, and seems to help. Telomeres protect the end of the chromosome from dna damage or from fusion with neighbouring chromosomes. Blocking telomerase kills cancer cells but provokes resistance, progression. But cancer cells get around this natural countdown by reactivating telomerase, an enzyme that rebuilds the. Recent patents on antitelomerase cancer therapy request pdf. The repression of telomerase and shorter telomeres in humans may have evolved, in part, as an anticancer protection mechanism. These observations suggest telomerase as an important target for the development of new anticancer drugs and strategies based on the reversal of tumor growth by telomerase inhibition summarized in table 1. The role of telomerase in cancer is best summarized by the car analogy. In different cell types, neoplastic transformation dramatically. Telomerase inhibition as cancer therapy sciencedirect. Role of telomeres and telomerase in aging and cancer.
Therefore, telomerase inhibitors, which destroy the capacity of telomerase containing cancer cells to replicate, can be applied as selective anticancer treatment. The development of a malignant cancer cell is only. Antitelomerase therapy provokes alt and mitochondrial. Special issue role of telomeres and telomerase in cancer. There are also various pitfalls for a use of telomerase as a therapeutic target in cancer treatment.
Longsought structure of telomerase paves way for drugs. Anti telomerase cancer treatment mainly includes rna interference, gene therapy, utilization of small molecule inhibitors, aiming at tert and the htr 1. The expression of telomerase in most cancer cells is directly proportional to the expression of htert mrna 54,55. First, with many but not all telomerase therapeutic approaches, one expects there will be a lag phase between the time telomerase is inhibited and the time telomeres of the cancer cells will have shortened sufficiently to produce detrimental effects on cellular proliferation. Telomerase and radiosensitivity of human tumors madame curie. To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in tcell lymphomas arising in atmmice engineered with an inducible telomerase reverse transcriptase allele. There is mounting evidence for the existence of an important relationship between telomeres and telomerase and cellular aging and cancer. Telomerase and drug resistance in cancer springerlink. Its been suggested that shortening the telomeres of cancer could be an effective treatment. Telomerase inhibitors as anticancer therapy bentham science.
Telomerase gene anti therapy stalls tumors growing in culture. A number of human tumors and cells immortalized in culture maintain their telomeres by a telomerase independent mechanism termed alternative lengthening of telomeres alt. Telomerase as a universal tumorassociated antigen for. It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs e. A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase. Telomerase activity as a marker of tumor cell survival to evaluate. A service of the national library of medicine, national institutes of health. Increased telomerase expression produces vulnerability of cancer cells, distinguishing them from normal cells in the body, although normal cells do also have some active telomerase. As demonstrated, this is one of the two key telomerase subunits that enable enzyme activity, detected mainly in cancer or stem cells. If telomerase is to be a target for anticancer therapies, it will be very important to know whether a particular tumor type requires the enzyme. A cancer cell is like a runaway car on the freeway. Dna determines much of who we are, but its not fixed for life. Eternal youth, cancer and telomeres fireside science.
Continued proliferation of tumor cells requires activation of telomerase to maintain chromosomal stability and extend. That would be similar to the activation of oncogenes that drive cancer cells to divide rapidly even when inappropriate. A ribonucleoprotein enzyme complex known as telomerase maintains telomere length in cancer cells by adding ttaggg repeats onto the telomeric ends. More than 30 years ago, when uc berkeley researchers discovered telomerase an enzyme that lengthens chromosome ends and prevents them from fraying enough to kill a cell speculation ran wild about its role in aging and cancer, setting off a fullcourt press to produce drugs to activate or block the enzyme. The htert gene encodes telomerase reverse transcriptase, the catalytic subunit of telomerase. Although the search for pharmacologic inhibitors of telomerase activity represents a promising approach for telomerase based anticancer therapy, the immunological properties of the telomerase. Three htert vaccines, gv1001, vx001 and grnvac1, have been used to elicit anti telomerase immune responses in cancer patients. Telomerase is active in gametes and most cancer cells, but is normally. This book summarizes experimental evidence and clinical data indicating that telomere dysfunction influences human ageing, diseases and cancer. Currently, many antitelomerase therapeutics are being evaluated in clinical trials against a variety of cancer types. Recent patents on antitelomerase cancer therapy bentham. Telomeres, telomerase and cancer reprint scientific. Studies to date have examined the mechanisms involved in the survival of cancer. Telomerase discovery paves way for drug development.
Abstract telomere length and telomerase activity are important factors in the. Cancer and ageing are flip sides of the same coin and telomerase, by and large, is doing the flipping. Roles of telomeres and telomerase in cancer, and advances. Two major strategies have been adopted to develop effective telomerase based immunotherapy in cancer. Proofofprinciple experiments using dominantnegative telomerase cells, antisense, or activesite inhibitors have shown that inhibition of telomerase in cancer cells can cause them to enter senescence and apoptosis. First, the anti proliferative effects of telomerase inhibition are induced in cells with short telomeres only, which requires some time of tumor growth until the drug can be effective. Telomerase inhibitors from natural products and their anticancer. Cancer is a condition in which certain cells in the body avoid dying. Blocking telomerase kills cancer cells but provokes. All of this information will be useful in future to design and. Telomerase and telomerebinding proteins are new potential targets for anticancer and anti ageing therapies. Inhibition of telomerase would be expected to result in the gradual erosion of the telomere due to the end replication problem. Unlimited cell growth is a hallmark of cancer, and studies have associated cancer with high telomerase activity. For incidence in breast cancer cells, there is a higher expression of htert mrna and protein without active telomerase 56.
The best evidence we have is that some other step is ratelimiting, because in practice, adding telomerase does not seem to increase cancer. Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The cellular machine mainly responsible for extending telomeres is the protein telomerase. Moreover, the relatively tumorspecific expression of telomerase is used to direct cytotoxic approaches, for instance cytotoxic lymphocytes or suicide gene expression, towards. Telomerase is commonly expressed in human cancer cells. Adding telomerase capacity to a cell will only cause the cell to progress toward cancer more rapidly if telomerase was the slowest step, the ratelimiting step. Fueled by telomerase, an enzyme that rebuilds telomeres after cell division, cancer cells are able to prevent telomere shortening, replicate without limitation, and conceivably live forever. The telomerase deficiency of human somatic cells reduces the risk of cancer development, as telomerase fuels uncontrolled cancer cell growth. Normal human cells progressively lose telomeres with each cell division until a few short telomeres become uncapped leading to. Therefore, an in vitro chemosensitivity assay, predicting the percentage of tumor cells killed by a panel of antitumor compounds, will provide the unique opportunity. Susan e hamilton and david r corey telomerase activity is upregulated in most types of malignant tumor. The telom erase rnp a nd telomere co mplex pr esent mult iple. There are several potential concerns that have been raised about telomerase as an anticancer target. Roles of telomeres and telomerase in cancer, and advances in.
A telomere is a region of repetitive sequences at each end of eukaryotic chromosomes in most eukaryotes. The relationship between mg and cancer is still a puzzle to disentangle. Inhibit telomerase, and you have a treatment for cancer, activate it and you prevent. Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a. Frontiers in clinical drug research anticancer agents should prove to be a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field. These cells are able to continually rebuild their telomeres after each division. Our behavior and environment can effect alterations to genes for good or ill. Thus, more sophisticated assays that do more than simply determine the presence or absence of telomerase will be required to determine whichif anyhuman cancers might require telomerase activity. Frontiers in clinical drug research anticancer agents.
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