Thymoquinone Induces Telomere Shortening, DNA Damage and Apoptosis in Human Glioblastoma Cells

Background: A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells. Methodology/Principal Findings: The cytotoxic effect of thymoquinone, a component derived from the plant Nigella sativa, was tested on human glioblastoma and normal cells. Our findings demonstrated that glioblastoma cells were more sensitive to thymoquinone-induced antiproliferative effects. Thymoquinone induced DNA damage, cell cycle arrest and apoptosis in the glioblastoma cells. It was also observed that thymoquinone facilitated telomere attrition by inhibiting the activity of telomerase. In addition to these, we investigated the role of DNA-PKcs on thymoquinone mediated changes in telomere length. Telomeres in glioblastoma cells with DNA-PKcs were more sensitive to thymoquinone mediated effects as compared to those cells deficient in DNA-PKcs. Conclusions/Significance: Our results indicate that thymoquinone induces DNA damage, telomere attrition by inhibiting telomerase and cell death in glioblastoma cells. Telomere shortening was found to be dependent on the status of DNA-PKcs. Collectively, these data suggest that thymoquinone could be useful as a potential chemotherapeutic agent in th

Telomere-Mediated Chromosomal Instability Triggers TLR4 Induced Inflammation and Death in Mice

BACKGROUND: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice) display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR) are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+), mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/-) mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups

Telomere-mediated genomic instability in cells from ataxia telangiectasia patients

Acta Medica Nagasakiensia53SUPPL.45-4

CSPG is a secreted factor that stimulates neural stem cell survival possibly by enhanced EGFR signaling

10.1371/journal.pone.0015341PLoS ONE512e1534

Optimization of cryopreservation of stem cells cultured as neurospheres: Comparison between vitrification, slow-cooling and raped cooling "freezing" protocols

Cryo-Letters286445-460CRLE

Human embryonic stem cells may display higher resistance to genotoxic stress as compared to primary explanted somatic cells

10.1089/scd.2007.0088Stem Cells and Development173599-607SCDT

Functional interplay of p53 and Mus81 in DNA damage responses and cancer

10.1158/0008-5472.CAN-07-1161Cancer Research67188527-8535CNRE

Involvement of mammalian Mus81 in genome integrity and tumor suppression

10.1126/science.1094557Science30456781822-1826SCIE

Progressive loss of epidermal growth factor receptor in a subpopulation of breast cancers: implications in target-directed therapeutics

10.1158/1535-7163.MCT-06-0809Molecular Cancer Therapeutics6112828-284

Chromosome 9 arm-specific telomere length and breast cancer risk

Background: Telomere dysfunction is involved in the development of breast cancer and very short telomeres are frequent genetic alterations in breast tumors. However, the influence of telomere lengths of specific chromosomal arms on the breast cancer risk is unknown. Methods: We conducted a case–control study of breast cancer to examine the associations of the telomere length on chromosome 9 short arms (9p) and long arms (9q) with risk of breast cancer. Chromosome 9 arm-specific telomere lengths were measured by quantitative fluorescent in situ hybridization using cultured blood lymphocytes. Results: Telomere length on chromosome 9p was significantly shorter in breast cancer patients than in control subjects (P < 0.001). Using the 50th percentile value in controls as a cut point, women who have short 9p telomeres had an increased risk of breast cancer [adjusted odds ratio (OR) = 2.6; 95% confidence interval (CI) = 1.5–4.3]. When the 9p telomere length was divided into quartiles, a significant inverse dose–response relationship between 9p telomere length and breast cancer risk was observed (Ptrend < 0.001), with a quartile ORs of 3.0 (95% CI = 1.2–7.5), 3.9 (95% CI = 1.6–9.5) and 6.6 (95% CI = 2.8–15.9) for third, second and first quartile, respectively, when compared with women in the fourth quartile. Conclusions: Short telomere length on chromosome 9p is strongly associated with the risk of breast cancer. If confirmed by future studies, chromosome 9p telomere length has the potential to be incorporated into the current prediction models to significantly enhance breast cancer risk prediction