Inhibition of Human Telomerase by 7-Deaza-2′-deoxyguanosine Nucleoside Triphosphate Analogs: Potent Inhibition by 6-Thio-7-deaza-2′-deoxyguanosine 5′-Triphosphate

Fletcher, Terace M.; Cathers, Brian E.; Ravikumar, K.S.; Mamiya, Blain M.; Kerwin, Sean M.

doi:10.1006/bioo.2000.1194

Cited by 49 publications

(24 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A diverse spectrum of nucleoside analogs, including 6-thio-7-deaza-2 0 -deoxyguanosine 5 0 -triphosphate ddGTP, ddATP, and ddTTP, have produced significant inhibition of telomerase activity in cell extracts, but have not been thoroughly tested in cell cultures or animal models [40]. Azydothymidine (AZT), an antiviral compound currently being used as a treatment for AIDS, produces effective inhibition of telomerase activity in multiple cell lines along with progressive telomere shortening and cytotoxic effects, both of which seem to be cell line dependent.…”

Section: Htert Inhibition By Nucleoside Analogs and Small Moleculesmentioning

confidence: 99%

Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity

2008

View full text Add to dashboard Cite

Telomeres, the specialized structures that comprise the ends of chromosomes, form a closed structure, or t-loop, that is important in preventing genomic instability. Forced modulation of this structure, via overexpression of a dominant-negative form of telomere repeat binding factor 2, a protein critical for maintaining t-loop structure, for example, can result in the activation of DNA-damage responses, and ultimately cellular senescence or apoptosis. This response is also seen in normal somatic cells, where telomeres steadily decrease in length as cellular proliferation occurs owing to inefficient replication of terminal telomeric DNA. When telomere length becomes critically short, t-loop structure is compromised, and the cell undergoes senescence. Telomerase, the enzyme responsible for telomere length maintenance, is overexpressed in a majority of cancers. Its lack of expression in most normal somatic cells makes it an attractive target in designing cancer therapeutics. Compounds currently under development that seek to inhibit hTERT, the reverse transcriptase component of telomerase, include nucleoside analogs and the small molecule BIBR1532. Compounds inhibiting the RNA component of telomerase, hTERC, include peptide nucleic acids, 2-5A antisense oligonucleotides, and N3'-P5' thio-phosphoramidates. Recently, an oligonucleotide sharing sequence homology with terminal telomeric DNA, termed 'T-oligo', has shown cytotoxic effects in multiple cancers in culture and animal models. Independent of telomerase function, T-oligo is thought to mimic the DNA-damage response a cell normally experiences when the telomere t-loop structure becomes dysfunctional. In this review, the molecular mechanisms attributed to telomerase inhibitors and T-oligo, as well as their potential as cancer therapeutics, are discussed.

show abstract

Section: Htert Inhibition By Nucleoside Analogs and Small Moleculesmentioning

confidence: 99%

Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity

2008

View full text Add to dashboard Cite

show abstract

“…On this basis, telomerase is the focus of attention as a marker of cancer and various approaches that target telomerase for anti-cancer therapy have been reported [98][99][100]. These approaches include antisense strategies that downregulate telomerase expression [101,102] or the use of telomerase inhibitors to inhibit telomerase activity [103,104]. Telomerase inhibition can also be achieved by the use of compounds that specifically interact with G4 DNA structures to prevent telomerase access to the necessary linear telomere substrate [98,[105][106][107][108].…”

Section: Targeting Enzymes That Metabolize Telomeric G4 Dna As a Mechmentioning

confidence: 99%

DNA Helicases as Targets for Anti-Cancer Drugs

Sharma

Doherty²,

Brosh³

2005

CMCACA

View full text Add to dashboard Cite

DNA helicases have essential roles in nucleic acid metabolism by facilitating cellular processes including replication, recombination, DNA repair, and transcription. The vital roles of helicases in these pathways are reflected by their emerging importance in the maintenance of genomic stability. Recently, a number of human diseases with cancer predisposition have been shown to be genetically linked to a specific helicase defect. This has led researchers to further investigate the roles of helicases in cancer biology, and to study the efficacy of targeting human DNA helicases for anti-cancer drug treatment. Helicase-specific inhibition in malignant cells may compromise the high proliferation rates of cancerous tissues. The role of RecQ helicases in response to replicational stress suggests a molecular target for selectively eliminating malignant tumor cells by a cancer chemotherapeutic agent. Alternate DNA secondary structures such as G-quadruplexes that may form in regulatory regions of oncogenes or G-rich telomere sequences are potential targets for cancer therapy since these sequence-specific structures are proposed to affect gene expression and telomerase activation, respectively. Small molecule inhibitors of G-quadruplex helicases may be used to regulate cell cycle progression by modulating promotor activation or disrupting telomere maintenance, important processes of cellular transformation. The design of small molecules which deter helicase function at telomeres may provide a molecular target since telomerase activity is necessary for the proliferation of numerous immortal cells. Although evidence suggests that helicases are specifically inhibited by certain DNA binding compounds, another area of promise in anti-cancer therapy is siRNA technology. Specific knockdown of helicase expression can be utilized as a means to sensitize oncogenic proliferating cell lines. This review will address these topics in detail and summarize the current avenues of research in anti-cancer therapy targeting helicases through small molecule inhibitors of DNA-protein complexes, DNA binding drugs, or down-regulation of helicase gene expression.

show abstract

“…also been used to detect and isolate cytotoxic compounds from plants (Alali et al, 1999). In addition, uncontrolled proliferation of cells has been linked to induction of the telomerase enzyme found in cancer cells and inhibition of this enzyme has been used to demonstrate the anticancer effects of catechins in tea and that of other small molecules (Naasani et al, 1998;Fletcher et al, 2001). Genotoxicity and mutagenic potential of plant extracts have also been evaluated by observing induced chromosomal aberrations in human lymphocytes and other proliferative cells (Patterson et al, 1987;Gadano et al, 2002).…”

Section: Introductionmentioning

confidence: 99%