scholarly journals The influence of compound itel1296 on telomerase activity and the growth of cancer cells

2011 ◽  
Vol 57 (5) ◽  
pp. 501-510 ◽  
Author(s):  
N.A. Kovalenko ◽  
D.D. Zhdanov ◽  
M.V. Bibikova ◽  
V.Y. Gotovtseva
Keyword(s):  
Cell Line ◽  
Fibroblast Cell ◽  
Telomerase Activity ◽  
Normal Fibroblast ◽  
Tumor Cell Lines ◽  
Sensitive Cell Line ◽  
Telomerase Inhibition ◽  
Telomerase Inhibitor ◽  
Telomerase Inhibitors ◽  
Promising Target

Telomerase is a ribonucleoprotein that synthesizes telomeric repeats and identified as a promising target for anticancer therapy. Here we describe a new compound aITEL1296 as a potent telomerase inhibitor. Its inhibitory activity was a bit higher (IC50 = 0,19±0,02 ng/ml) than that of BIBR1532, one of the most potent telomerase inhibitors known to date. Besides telomerase inhibition aITEL1296 activated apoptotic mechanisms and effectively suppressed proliferation of tumor cell lines (GI50 = 5,0±0,2 ng/ml for most sensitive cell line LnCap) but not normal fibroblast cell line.

scholarly journals In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

2022 ◽  
Vol 15 (1) ◽  
pp. 82
Author(s):  
Giulia Culletta ◽  
Mario Allegra ◽  
Anna Maria Almerico ◽  
Ignazio Restivo ◽  
Marco Tutone
Keyword(s):  
Cell Line ◽  
Active Site ◽  
Cancer Therapeutics ◽  
Telomerase Activity ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Reverse Transcriptase Enzyme ◽  
Telomerase Inhibitor ◽  
Telomerase Inhibitors ◽  
Promising Target

Telomerase, a reverse transcriptase enzyme involved in DNA synthesis, has a tangible role in tumor progression. Several studies have evidenced telomerase as a promising target for developing cancer therapeutics. The main reason is due to the overexpression of telomerase in cancer cells (85–90%) compared with normal cells where it is almost unexpressed. In this paper, we used a structure-based approach to design potential inhibitors of the telomerase active site. The MYSHAPE (Molecular dYnamics SHared PharmacophorE) approach and docking were used to screen an in-house library of 126 arylsulfonamide derivatives. Promising compounds were synthesized using classical and green methods. Compound 2C revealed an interesting IC50 (33 ± 4 µM) against the K-562 cell line compared with the known telomerase inhibitor BIBR1532 IC50 (208 ± 11 µM) with an SI ~10 compared to the BALB/3-T3 cell line. A 100 ns MD simulation of 2C in the telomerase active site evidenced Phe494 as the key residue as well as in BIBR1532. Each moiety of compound 2C was involved in key interactions with some residues of the active site: Arg557, Ile550, and Gly553. Compound 2C, as an arylsulfonamide derivative, is an interesting hit compound that deserves further investigation in terms of optimization of its structure to obtain more active telomerase inhibitors

scholarly journals Berberine Inhibits Telomerase Activity and Induces Cell Cycle Arrest and Telomere Erosion in Colorectal Cancer Cell Line, HCT 116

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 376
Author(s):  
Muhammad Azizan Samad ◽  
Mohd Zuwairi Saiman ◽  
Nazia Abdul Majid ◽  
Saiful Anuar Karsani ◽  
Jamilah Syafawati Yaacob
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Line ◽  
Cancer Cell ◽  
Telomerase Activity ◽  
Telomerase Inhibitor ◽  
Telomerase Inhibitors ◽  
Hct 116 ◽  
Human Telomerase ◽  
Telomere Erosion

Colorectal cancer (CRC) is the most common cancer among males and females, which is associated with the increment of telomerase level and activity. Some plant-derived compounds are telomerase inhibitors that have the potential to decrease telomerase activity and/or level in various cancer cell lines. Unfortunately, a deeper understanding of the effects of telomerase inhibitor compound(s) on CRC cells is still lacking. Therefore, in this study, the aspects of telomerase inhibitors on a CRC cell line (HCT 116) were investigated. Screening on HCT 116 at 48 h showed that berberine (10.30 ± 0.89 µg/mL) is the most effective (lowest IC50 value) telomerase inhibitor compared to boldine (37.87 ± 3.12 µg/mL) and silymarin (>200 µg/mL). Further analyses exhibited that berberine treatment caused G0/G1 phase arrest at 48 h due to high cyclin D1 (CCND1) and low cyclin-dependent kinase 4 (CDK4) protein and mRNA levels, simultaneous downregulation of human telomerase reverse transcriptase (TERT) mRNA and human telomerase RNA component (TERC) levels, as well as a decrease in the TERT protein level and telomerase activity. The effect of berberine treatment on the cell cycle was time dependent as it resulted in a delayed cell cycle and doubling time by 2.18-fold. Telomerase activity and level was significantly decreased, and telomere erosion followed suit. In summary, our findings suggested that berberine could decrease telomerase activity and level of HCT 116, which in turn inhibits the proliferative ability of the cells.

scholarly journals Phytochemical Analysis and In Vitro Effects of Allium fistulosum L. and Allium sativum L. Extracts on Human Normal and Tumor Cell Lines: A Comparative Study

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 574
Author(s):  
Adrian Bogdan Țigu ◽  
Cristian Silviu Moldovan ◽  
Vlad-Alexandru Toma ◽  
Anca Daniela Farcaș ◽  
Augustin Cătălin Moț ◽  
...  
Keyword(s):  
Cell Line ◽  
Allium Sativum ◽  
Allium Fistulosum ◽  
Tumor Cell Lines ◽  
Sensitive Cell ◽  
Sensitive Cell Line ◽  
Welsh Onion ◽  
Normal Cells ◽  
Ic50 Value ◽  
High Concentrations

Allium sativum L. (garlic bulbs) and Allium fistulosum L. (Welsh onion leaves) showed quantitative differences of identified compounds: allicin and alliin (380 µg/mL and 1410 µg/mL in garlic; 20 µg/mL and 145 µg/mL in Welsh onion), and the phenolic compounds (chlorogenic acid, p-coumaric acid, ferulic acid, gentisic acid, 4-hydroxybenzoic acid, kaempferol, isoquercitrin, quercitrin, quercetin, and rutin). The chemical composition determined the inhibitory activity of Allium extracts in a dose-dependent manner, on human normal cells (BJ-IC50 0.8841% garlic/0.2433% Welsh onion and HaCaT-IC50 1.086% garlic/0.6197% Welsh onion) and tumor cells (DLD-1-IC50 5.482%/2.124%; MDA-MB-231-IC50 6.375%/2.464%; MCF-7-IC50 6.131%/3.353%; and SK-MES-1-IC50 4.651%/5.819%). At high concentrations, the cytotoxic activity of each extract, on normal cells, was confirmed by: the 50% of the growth inhibition concentration (IC50) value, the cell death induced by necrosis, and biochemical determination of LDH, catalase, and Caspase-3. The four tumor cell lines treated with high concentrations (10%, 5%, 2.5%, and 1.25%) of garlic extract showed different sensibility, appreciated on the base of IC50 value for the most sensitive cell line (SK-MES-1), and the less sensitive (MDA-MB-231) cell line. The high concentrations of Welsh onion extract (5%, 2.5%, and 1.25%) induced pH changes in the culture medium and SK-MES-1 being the less sensitive cell line.

GRN163L Inhibits Telomerase Activity in B-CLL Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5041-5041 ◽  
Author(s):  
Claudia Lin ◽  
Rajendra N. Damle ◽  
Nicholas Chiorazzi ◽  
Allison C. Chin
Keyword(s):  
Hematologic Malignancies ◽  
Telomerase Activity ◽  
Lymphocytic Leukemia ◽  
Telomerase Inhibition ◽  
Nuclear Compartments ◽  
Telomerase Inhibitor ◽  
Effective Inhibition ◽  
Xenograft Models

Abstract B-CLL cells, like many solid and hematologic malignancies, are characterized by short telomeres, suggesting that they would be acutely susceptible to telomerase inhibition. We and others have documented that CLL patients in poorer prognosis subsets, i.e., those without IgVH mutations, had shorter mean telomere lengths and higher telomerase levels than patients with IgVH mutations (Damle et al, 2004; Keating et al, 2003; Bechter et al 1998, Hultdin et al, 2003). Treatment with the telomerase inhibitor GRN163L, a lipid-conjugated 13-mer thio-phosphoramidate oligonucleotide (Geron Corporation), inhibits the growth of human hepatoma (Djojosubroto et al, 2005), ovarian carcinoma (Ertem et al, 2004, 2005), and multiple myeloma (CAG, MM.1S) cell lines in vitro and in vivo (AACR 2004 and 2005 Annual Meetings). Although no validated human B-CLL xenograft models exist, preliminary data indicate effective inhibition of telomerase in freshly thawed B-CLL cells upon exposure to GRN163L. We will present data demonstrating robust uptake of GRN163L into primary B-CLL patient cells, along with the subcellular distribution of the oligonucleotide into cytoplasmic and nuclear compartments. Comparison of the effect of GRN163L and a mismatch oligonucleotide control on telomerase inhibition will be described. Geron initiated a Phase I/II trial with GRN163L in chronic lymphocytic leukemia in July 2005.

A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2606-2614 ◽  
Author(s):  
Rosario Machado-Pinilla ◽  
Isabel Sánchez-Pérez ◽  
José Ramón Murguía ◽  
Leandro Sastre ◽  
Rosario Perona
Keyword(s):  
Cisplatin Resistance ◽  
Telomerase Activity ◽  
Dyskeratosis Congenita ◽  
Target Sequence ◽  
Premature Senescence ◽  
Dependent Manner ◽  
Telomerase Inhibition ◽  
Telomerase Inhibitors ◽  
In Vitro Exposure

Dyskerin gene is mutated in patients with X-linked dyskeratosis congenita (X-DC), which results in greatly reduced levels of telomerase activity. A genetic suppressor element (GSE) termed GSE24-2 has been isolated in a screening for cisplatin resistance. GSE24-2–expressing cells presented impaired telomerase inhibition following in vitro exposure to chemotherapies, such as cisplatin, or telomerase inhibitors. The promoter of the telomerase component hTERT was constitutively activated in GSE24-2 cells in a c-myc expression–dependent manner. Deletion analyses and mutagenesis of the human c-myc promoter demonstrated that the target sequence for activation was the nuclease hypersensitive element-III (NHEIII) site located upstream to the P1 region of the promoter. Further, expression of GSE24-2 in cell lines derived from patients with X-DC and in VA13 cells induced increased hTERT RNA and hTR levels and recovery of telomerase activity. Finally, expression of GSE24-2 was able to rescue X-DC fibroblasts from premature senescence. These data demonstrate that this domain of dyskerin plays an important role in telomerase maintenance following cell insults such as cisplatin treatment, and in telomerase-defective cells in patients with X-DC. The expression of this dyskerin fragment has a dominant function in X-DC cells and could provide the basis for a therapeutic approach to this disease.

scholarly journals Quantitative Biology of Human Shelterin and Telomerase: Searching for the Weakest Point

2019 ◽  
Vol 20 (13) ◽  
pp. 3186 ◽  
Author(s):  
Veverka ◽  
Janovič ◽  
Hofr
Keyword(s):  
Structural Information ◽  
Anticancer Therapy ◽  
Telomerase Activity ◽  
Future Research ◽  
Quantitative Biology ◽  
Telomeric Dna ◽  
Telomerase Inhibition ◽  
Promising Target ◽  
The Status ◽  
Associated Proteins

The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent works have provided new insights into the mechanisms of how human shelterin assembles and recruits telomerase to telomeres. Inhibition of telomerase activity and telomerase recruitment to chromosome ends is a promising target for anticancer therapy. Here, we summarize results of quantitative assessments and newly emerged structural information along with the status of the most promising approaches to telomerase inhibition in cancer cells. We focus on the mechanism of shelterin assembly and the mechanisms of how shelterin affects telomerase recruitment to telomeres, addressing the conceptual dilemma of how shelterin allows telomerase action and regulates other essential processes. We evaluate how the identified critical interactions of telomerase and shelterin might be elucidated in future research of new anticancer strategies.

scholarly journals Coexistence of Alternative Lengthening of Telomeres and Telomerase in hTERT-Transfected GM847 Cells

2001 ◽  
Vol 21 (12) ◽  
pp. 3862-3875 ◽  
Author(s):  
Kilian Perrem ◽  
Lorel M. Colgin ◽  
Axel A. Neumann ◽  
Thomas R. Yeager ◽  
Roger R. Reddel
Keyword(s):  
Cell Line ◽  
Telomerase Activity ◽  
Promyelocytic Leukemia ◽  
Tumor Cell Lines ◽  
Hybrid Cells ◽  
Alternative Lengthening Of Telomeres ◽  
Positive Tumor Cell ◽  
Alternative Lengthening ◽  
Pml Bodies ◽  
Population Doublings

ABSTRACT It has been shown previously that some immortalized human cells maintain their telomeres in the absence of significant levels of telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Cells utilizing ALT have telomeres of very heterogeneous length, ranging from very short to very long. Here we report the effect of telomerase expression in the ALT cell line GM847. Expression of exogenous hTERT in GM847 (GM847/hTERT) cells resulted in lengthening of the shortest telomeres; this is the first evidence that expression of hTERT in ALT cells can induce telomerase that is active at the telomere. However, rapid fluctuation in telomere length still occurred in the GM847/hTERT cells after more than 100 population doublings. Very long telomeres and ALT-associated promyelocytic leukemia (PML) bodies continued to be generated, indicating that telomerase activity induced by exogenous hTERT did not abolish the ALT mechanism. In contrast, when the GM847 cell line was fused with two different telomerase-positive tumor cell lines, the ALT phenotype was repressed in each case. These hybrid cells were telomerase positive, and the telomeres decreased in length, very rapidly at first and then at the rate seen in telomerase-negative normal cells. Additionally, ALT-associated PML bodies disappeared. After the telomeres had shortened sufficiently, they were maintained at a stable length by telomerase. Together these data indicate that the telomerase-positive cells contain a factor that represses the ALT mechanism but that this factor is unlikely to be telomerase. Further, the transfection data indicate that ALT and telomerase can coexist in the same cells.

scholarly journals Cytotoxicity and Cellular Uptake of 5-Fluorouracil Loaded Methylcellulose Nanohydrogel for Treatment of Oral Cancer

2020 ◽  
Vol 10 (1) ◽  
pp. 1904-1918
Keyword(s):  
Oral Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cellular Uptake ◽  
Sol Gel ◽  
Cancer Cell Line ◽  
Fibroblast Cell ◽  
Vero Cells ◽  
Normal Fibroblast ◽  
Physical Crosslinking

The objective of the study was to investigate the cytotoxicity and cellular uptake of prepared 5-Fluorouracil (5-FU) nano hydrogel formulation using KB oral cancer cell line and VERO fibroblast cell line. The biodegradable thermoresponsive modified methylcellulose (MMC) polymer was used for the preparation of nano hydrogel, whereas it shows a sol-gel phase transition at 36˚C to 40˚C. The physical crosslinking method was used, followed by probe sonication for the preparation of 5-FU loaded MMC nano hydrogel. The mechanism of crosslinking was studied by FT-IR and SEM. These experimental techniques explained physical crosslinking viz. H-bonding phenomenon with the interconnected porous structure of nanoscale pore size. Cytotoxicity assay in the concentration range from 1 µg/ml to 2000µg/ml shows an IC50 value at around 250µg/ml. This nano hydrogel shows concentration-dependent toxicity to the cancer cells while they were less toxic to normal fibroblast VERO cells. Cellular uptake was confirmed by the green fluorescence inside cells by Rhodamine-B conjugation using a fluorescent microscope. These results depict that 5-FU loaded thermosensitive nano hydrogel may be a promising candidate for intratumoral targeted drug delivery to cancer cells.

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