Dynamics of telomeric chromatin at the crossroads of aging and cancer

2010 ◽  
Vol 48 ◽  
pp. 147-164 ◽  
Author(s):  
Jing Ye ◽  
Yunlin Wu ◽  
Eric Gilson
Keyword(s):  
Chromosomal Instability ◽  
Cellular Proliferation ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Telomere Dysfunction ◽  
Promising Candidate ◽  
Telomere Shortening ◽  
Anti Cancer ◽  
Protein Components

Telomeres are nucleoprotein structures that protect the ends of human chromosomes through the formation of a ‘cap’, thus preventing exonucleolytic degradation, inter- and intra-chromosomal fusion, and subsequent chromosomal instability. During aging, telomere shortening correlates with tissue dysfunction and loss of renewal capacity. In human cancer, telomere dysfunction is involved in early chromosome instability, long-term cellular proliferation, and possibly other processes related to cell survival and microenvironment. Telomeres constitute an attractive target for the development of novel small-molecule anti-cancer drugs. In particular, individual protein components of the core telomere higher-order chromatin structure (known as the telosome or ‘shelterin’ complex) are promising candidate targets for cancer therapy.

scholarly journals Evaluation of the Anti-Inflammatory and Anti-Oxidative Effects of Therapeutic Human Lactoferrin Fragments

2021 ◽  
Vol 9 ◽  
Author(s):  
Yu Pan ◽  
Zhao Liu ◽  
Yijie Wang ◽  
Linshen Zhang ◽  
Niying Chua ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Skin Inflammation ◽  
Medical Regimen ◽  
Anti Cancer ◽  
Colorectal Cancer Cells ◽  
Inflammatory Bowel ◽  
Therapeutic Properties ◽  
Anti Inflammatory ◽  
Oxidative Effects

Chronic inflammation is considered a pressing health issue that needs resolving. Inflammatory disease such as inflammatory bowel disease requires a long-term medical regimen to prevent disease progression. Conventionally, lactoferrin is used to treat mild gastrointestinal tract and skin inflammation. Protease-digested lactoferrin fragments often exhibit improved therapeutic properties compared to full-length lactoferrin (flHLF). However, there are no studies on the use of protease-digested lactoferrin fragments to treat inflammation. Herein, we assess the anti-inflammatory properties of engineered recombinant lactoferrin fragments (rtHLF4, rteHLF1, and rpHLF2) on non-malignant colonic fibroblast cells and colorectal cancer cells. We found that rtHLF4 is 10 times more effective to prevent inflammation compared to flHLF. These results were investigated by looking into the reactive oxygen species (ROS) production, angiogenesis activity, and cellular proliferation of the treated cells. We have demonstrated in this study the anti-inflammatory properties of the flHLF and the various lactoferrin fragments. These results complement the anti-cancer properties of these proteins that were demonstrated in an earlier study.

scholarly journals Dormant replication origin firing links replication stress to whole chromosomal instability in human cancer

2021 ◽  
Author(s):  
Ann-Kathrin Schmidt ◽  
Nicolas Boehly ◽  
Xiaoxiao Zhang ◽  
Benjamin O. Slusarenko ◽  
Magdalena Hennecke ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Chromosomal Instability ◽  
Replication Origin ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Replication Stress ◽  
S Phase ◽  
Origin Firing ◽  
Human Cancer Cells ◽  
Chromosome Missegregation

Chromosomal instability (CIN) is a hallmark of cancer and comprises structural CIN (S-CIN) and whole chromosome instability (W-CIN). Replication stress (RS), a condition of slowed or stalled DNA replication during S phase, has been linked to S-CIN, whereas defects in mitosis leading to chromosome missegregation and aneuploidy can account for W-CIN. It is well established that RS can activate additional replication origin firing that is considered as a rescue mechanism to suppress chromosomal instability in the presence of RS. In contrast, we show here that an increase in replication origin firing during S phase can contribute to W-CIN in human cancer cells. Increased origin firing can be specifically triggered by overexpression of origin firing genes including GINS1 and CDC45, whose elevated expression significantly correlates with W-CIN in human cancer specimens. Moreover, endogenous mild RS present in cancer cells characterized by W-CIN or modulation of the origin firing regulating ATR-CDK1-RIF1 axis induces dormant origin firing, which is sufficient to trigger chromosome missegregation and W-CIN. Importantly, chromosome missegregation upon increased dormant origin firing is mediated by increased microtubule growth rates leading to the generation of lagging chromosomes in mitosis, a condition prevalent in chromosomally unstable cancer cells. Thus, our study identified increased or dormant replication origin firing as a hitherto unrecognized, but cancer-relevant trigger for chromosomal instability.

scholarly journals The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells

Oncogene ◽  
2020 ◽  
Author(s):  
Ann-Kathrin Schmidt ◽  
Karoline Pudelko ◽  
Jan-Eric Boekenkamp ◽  
Katharina Berger ◽  
Maik Kschischo ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Tumor Suppressor Genes ◽  
Chromosomal Instability ◽  
Target Gene ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Microtubule Assembly ◽  
Cdk Inhibitor ◽  
Human Cancer Cells

Abstract Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.

scholarly journals Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells

2012 ◽  
Vol 10 (32) ◽  
pp. 6537 ◽  
Author(s):  
Sebastian Müller ◽  
Deborah A. Sanders ◽  
Marco Di Antonio ◽  
Stephanos Matsis ◽  
Jean-François Riou ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cancer Cells ◽  
Human Cancer ◽  
Telomere Dysfunction ◽  
Human Cancer Cells

Molecular Targets, Anti-cancer Properties and Potency of Synthetic Indole-3-carbinol Derivatives

2019 ◽  
Vol 19 (7) ◽  
pp. 540-554 ◽  
Author(s):  
Mojgan Noroozi Karimabad ◽  
Mehdi Mahmoodi ◽  
Abdolah Jafarzadeh ◽  
Ali Darekordi ◽  
Mohamad Reza Hajizadeh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cellular Proliferation ◽  
Human Cancer ◽  
Molecular Targets ◽  
Tumor Formation ◽  
Mesenchymal Transition ◽  
Anti Cancer

The indole-3-carbinol (I3C) displays anti-cancer/proliferative activities against human cancer cells. Cellular proliferation is an event associated with the progress and its continuation. This manifest is described by variation in expression and/or functions of genes that are related with cell cycle relevant proteins. The constitutive activation of several signal transduction pathways stimulates cells proliferation as well. The immediate stages in cancer development are accompanied by a fibrogenic response and the progression of the hypoxic environment is in favor of survival and proliferatory functions of cancer stem cells. A main part for prevention of in cancer cells death may manifest through altering cell metabolism. Cellular proliferation and metastasis are reported to be supported with increased generation of responsible hormones (in hormone dependent malignancies), and further promotion the angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as via taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, NF-κB, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), phosphoinositide 3 kinase/Akt, Wnt, cell cycle related protein, with androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in association with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may serve as markers for early diagnosis and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. In particular, I3C and DIM have been extensively investigated for their importance against numbers human cancers both in vitro and in vivo. We aimed the present manuscript, current study, to review anticancer properties and the miscellaneous mechanisms underlying the antitumorigenicity in an in-depth study for broadening the I3C treating marvel.

scholarly journals Development of NOSH-NSAIDs: a new class of anti-inflammatory pharmaceuticals for the treatment of cancer

2017 ◽  
Vol 39 (4) ◽  
pp. 24-29
Author(s):  
Khosrow Kashfi
Keyword(s):  
Human Cancer ◽  
Tumour Mass ◽  
Human Cancer Cell Lines ◽  
New Class ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Better Than

Non-steroidal anti-inflammatory drugs (NSAIDs) have anti-cancer (chemopreventive) properties; however, side effects preclude their long-term use. NOSH-NSAIDs, designed as safer alternatives, are novel hybrid chimaeras that release nitric oxide (NO) and hydrogen sulfide (H2S). NOSH-NSAIDs are gastrointestinally safe yet retain all the pharmacological properties of their native NSAID. NOSHNSAIDs are orders of magnitude more potent than their conventional counterparts in inhibiting the growth of various human cancer cell lines of different tissue origins, adenomatous, epithelial and lymphocytic. This growth inhibition is a result of a reduction in cell proliferation and cell cycle arrest, leading to increased apoptosis. In xenograft mouse models of cancer, NOSH-aspirin was better than normal aspirin as a chemopreventive agent; it dose-dependently inhibited tumour growth and tumour mass. NOSH-naproxen was significantly more efficacious than normal naproxen in reducing the growth of established tumours.

scholarly journals Angiogenesis Inhibitors as Anti-Cancer Therapy Following Renal Transplantation: A Case Report and Review of the Literature

2021 ◽  
Vol 28 (1) ◽  
pp. 661-670
Author(s):  
Lawrence Kasherman ◽  
Jeffrey Doi ◽  
Katherine Karakasis ◽  
Jeffrey Schiff ◽  
Abhijat Kitchlu ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Organ Transplant ◽  
Angiogenesis Inhibitors ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Immunosuppressive Medication ◽  
Increased Risk ◽  
Anti Cancer ◽  
Solid Organ Transplant Recipients

Solid organ transplant recipients on long-term immunosuppressive medication are at increased risk of developing malignancy, and treatment of advanced cancers with angiogenesis inhibitors in this context has not been widely studied. We present a case of recurrent high-grade serous ovarian carcinoma treated with paclitaxel and bevacizumab in the context of prior renal transplantation where the patient responded well to treatment with controlled toxicities, discussing the potential for increased rates of adverse events and drug interactions in this select population.

scholarly journals DNA-Replikationsstress, Mitose und genomische Instabilität

BIOspektrum ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 10-13
Author(s):  
Alicia Konrath ◽  
Ann-Kathrin Schmidt ◽  
Holger Bastians
Keyword(s):  
Dna Replication ◽  
Tumor Progression ◽  
Chromosome Aberrations ◽  
Chromosomal Instability ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Functional Link ◽  
Structural Chromosome ◽  
Genomische Instabilität

AbstractChromosomal instability (CIN) is a hallmark of cancer and contributes to tumorigenesis and tumor progression. While structural CIN (S-CIN) leads to structural chromosome aberrations, whole chromosome instability (W-CIN) is defined by perpetual gains or losses of chromosomes during mitosis causing aneuploidy. Mitotic defects, but also abnormal DNA replication (replication stress) can lead to W-CIN. However, the functional link between replication stress, mitosis and aneuploidy is little understood.

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