Telomerase Inhibition in Cancer Therapeutics: Molecular-Based Approaches

Publisher, Bentham Science Publisher Bentham Science

doi:10.2174/092986706778521887

Cited by 46 publications

(17 citation statements)

References 87 publications

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“…73 Overcoming the cell cycle arrest signals of critically short telomeres has been found to be challenged by cancer cells. 74 If telomerase is activated, telomere length can be restored, and the otherwise normal stop on proliferation control might be overridden.…”

Section: Molecular Pathways Linking Cancer and Agingmentioning

confidence: 99%

Bladder cancer in the elderly

Shariat¹,

Milowsky²,

Droller³

2009

Urologic Oncology: Seminars and Original Investigations

182

126

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Introduction Age is now widely accepted as the greatest single risk factor for developing bladder cancer, and bladder cancer is considered as primarily a disease of the elderly. Because of the close link between age and incidence of bladder cancer, it can be expected that this disease will become an enormous challenge with the growth of an aging population in the years ahead. Methods Using MEDLINE, a search of the literature between January 1966 and July 2007 was performed to describe normative physiologic changes associated with aging, elucidate genetic and epigenetic alterations that associate aging with bladder cancer and its phenotypes; and to characterize how aging influences efficacies, risks, side effects and potential complications of the treatments needed for the various stages of bladder cancer.. Results We discuss influence of aging on host physiology, genetic and epigenetic changes, environmental influences, and host factors in the development and treatment of bladder cancer. Treatments with intravesical Bacille Calmette Guerin, radical cystectomy, and perioperative chemotherapy are less well tolerated and have poorer response in elderly patients compared to their younger counterparts. Elderly patients face both clinical and broader institutional barriers to appropriate treatment and may receive less aggressive treatment and sub-therapeutic dosing. However, when appropriately selected, elderly patients tolerate and respond well to cancer treatments. Conclusions The decision to undergo treatment for cancer is a tradeoff between loss of function and/or independence and extension of life which is complicated by a host of concomitant issues such as co-morbid medical conditions, functional declines and “frailty”, family dynamics, and social and psychological issues. Chronological age should not preclude definitive surgical therapy. It is imperative that healthcare practitioners and researchers from disparate disciplines collectively focus efforts towards gaining a better understanding of what the consequences of bladder cancer and its treatments are for older adults and how to appropriately meet the multifaceted medical and psychosocial needs of this growing population.

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Section: Molecular Pathways Linking Cancer and Agingmentioning

confidence: 99%

Bladder cancer in the elderly

Shariat¹,

Milowsky²,

Droller³

2009

Urologic Oncology: Seminars and Original Investigations

182

126

View full text Add to dashboard Cite

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“…Therefore, it is likely that EGCG imparts its chemopreventive effects through many different mechanisms (8–10). One mechanism includes the inhibition of human telomerase reverse transcriptase ( hTERT ), the catalytic subunit of telomerase, an important enzyme required for maintenance of telomere length and tumorigenesis (2, 11, 12). Inhibition of telomerase has received wide attention in cancer prevention because of its high expression in cancer cells and very low expression in normal somatic cells (11–13).…”

Section: Introductionmentioning

confidence: 99%

“…One mechanism includes the inhibition of human telomerase reverse transcriptase ( hTERT ), the catalytic subunit of telomerase, an important enzyme required for maintenance of telomere length and tumorigenesis (2, 11, 12). Inhibition of telomerase has received wide attention in cancer prevention because of its high expression in cancer cells and very low expression in normal somatic cells (11–13). Furthermore, there has been growing interest in epigenetic regulation by EGCG in chemoprevention due to its DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) inhibition activities (14–16).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Prodrug of Epigallocatechin-3-gallate: Differential Epigenetic hTERT Repression in Human Breast Cancer Cells

Meeran

Patel

Chan

et al. 2011

Cancer Prevention Research

129

117

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Epigallocatechin-3-gallate (EGCG), a major component of green tea polyphenols (GTPs), has been reported to down-regulate telomerase activity in breast cancer cells thereby increasing cellular apoptosis and inhibiting cellular proliferation. However, the major concerns with GTPs are their bioavailability and stability under physiological conditions. In the present study, we show that treatments with EGCG and a novel pro-drug of EGCG (pEGCG) dose- and time-dependently inhibited the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells but not normal control MCF10A cells. Further, both EGCG and Pro-EGCG inhibited the transcription of hTERT (human telomerase reverse transcriptase), the catalytic subunit of telomerase, through epigenetic mechanisms in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells. The down-regulation of hTERT expression was found to be due to hTERT promoter hypomethylation and histone deacetylations, mediated at least partially through inhibition of DNA methyltransferase and histone acetyltransferase activities, respectively. In addition, we also observed that EGCG and pEGCG can remodel chromatin structures of the hTERT promoter by decreasing the level of acetyl-H3, acetyl-H3K9 and acetyl-H4 to the hTERT promoter. EGCG and pEGCG induced chromatin alterations that facilitated the binding of many hTERT repressors such as MAD1 and E2F-1 to the hTERT regulatory region. Depletion of E2F-1 and MAD1 using siRNA reversed the pEGCG down-regulated hTERT expression and associated cellular apoptosis differently in ER-positive and ER-negative breast cancer cells. Collectively, our data provide new insights into breast cancer prevention through epigenetic modulation of telomerase by using Pro-EGCG, a more stable form of EGCG, as a novel chemopreventive compound.

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“…Modifications of traditional antisense oligonucleotides used in telomerase inhibition include 2'-5'-oligoadenylate, 2'- O -methyl-RNA, phosphorothioate-modified oligodeoxynucleotides [PS-ODN], peptide nucleic acids [PNA] (Fig. 2B ), and locked nucleic acids [LNA] [47]. PU27 is a sequence specific DNA oligoclenucleotide currently in preclinical stage for a wide variety of tumor type including leukemia, prostate cancer, renal cancer and breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Telomerase as a Cancer Target. Development of New Molecules

Gómez¹,

Armando²,

Cerrudo³

et al. 2016

CTMC

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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.

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Telomerase Inhibition in Cancer Therapeutics: Molecular-Based Approaches

Cited by 46 publications

References 87 publications

Bladder cancer in the elderly

Bladder cancer in the elderly

A Novel Prodrug of Epigallocatechin-3-gallate: Differential Epigenetic hTERT Repression in Human Breast Cancer Cells

Telomerase as a Cancer Target. Development of New Molecules

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