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Therapeutic targeting of replicative immortality

Journal Article · · Seminars in Cancer Biology
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [9];  [3];  [10];  [11];  [11];  [12];  [13];  [14];  [15];  [16];  [17];  [18] more »;  [19];  [20];  [21];  [17];  [22];  [13];  [18];  [14];  [23];  [15] « less
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; DOE/OSTI
  2. Children's Cancer Inst. Australia, Kensington, NSW (Australia)
  3. Univ. of Glasgow, Scotland (United Kingdom)
  4. Old Dominion Univ., Norfolk, VA (United States)
  5. Univ. of Montreal, QC (Canada)
  6. Washington State Univ., Pullman, WA (United States)
  7. Univ. of California, Berkeley, CA (United States)
  8. Biodonostia Inst., Gipuzkoa (Spain)
  9. Universdad de Sevilla, Seville (Spain). Consejo Superior de Investigaciones Cientificas. Inst. de Biomedicina de Sevilla
  10. Sentara Healthcare, Norfolk, VA (United States)
  11. Nara Medical Univ., Kashihara, Nara (Japan)
  12. National Technical Univ. of Athens (Greece)
  13. Univ. of Florence (Italy)
  14. United Arab Emirates Univ., Al Ain (United Arab Emirates); Cairo Univ. (Egypt)
  15. Univ. of Illinois at Urbana-Champaign, IL (United States)
  16. Creighton Univ., Omaha, NE (United States)
  17. SASTRA Univ., Thanjavur, Tamil Nadu (India)
  18. Tor Vergata Univ. of Rome (Italy)
  19. Ovarian and Prostate Cancer Research Trust, Guildford, Surrey (United Kingdom)
  20. Purdue Univ., West Lafayette, IN (United States)
  21. Wayne State Univ., Detroit, MI (United States). Karmanos Cancer Inst.
  22. New York Medical College, Valhalla, NY (United States)
  23. Mayo Clinic, Rochester, MN (United States)
+ Show Author Affiliations

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1623713
Journal Information:
Seminars in Cancer Biology, Journal Name: Seminars in Cancer Biology Journal Issue: S Vol. 35; ISSN 1044-579X
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

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Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts journal March 1998
The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2 journal June 1998
Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process journal July 1999
Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras journal September 1999
p16INK4a can initiate an autonomous senescence program journal March 2000
Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954 journal November 2001
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Oligonucleotide N3′→P5′ phosphoramidates as efficient telomerase inhibitors journal January 2002
Telomerase as a universal tumor-associated antigen for cancer immunotherapy journal January 2002
Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway journal June 2002
Telomere dysfunction and telomerase reactivation in human leukemia cell lines after telomerase inhibition by the expression of a dominant-negative hTERT mutant journal November 2002
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Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways journal August 2003
Differences in stability of repressor complexes at promoters underlie distinct roles for Rb family members journal January 2004
Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappaB and induction of apoptosis journal December 2003
Absence of p21WAF1 cooperates with c-myc in bypassing Ras-induced senescence and enhances oncogenic cooperation journal June 2004
Tumor necrosis factor alpha induces senescence and chromosomal instability in human leukemic cells journal August 2004
Lipid modification of GRN163, an N3′ → P5′ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition journal May 2005
Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms journal September 2005
Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia journal May 2006
BRAFE600 in benign and malignant human tumours journal August 2007
DNA damage signalling guards against activated oncogenes and tumour progression journal December 2007
Many roads lead to oncogene-induced senescence journal January 2008
Inhibition of telomerase activity with hTERT antisense increases the effect of CDDP-induced apoptosis in myeloid leukemia journal January 2002
Novel polyoxazole-based cyclopeptides from Streptomyces sp. Total synthesis of the cyclopeptide YM-216391 and synthetic studies towards telomestatin journal January 2008
Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea: EGCG inhibition of tumour invasion and angiogenesis journal December 2001
Inhibition of Telomerase Activity by a Hammerhead Ribozyme Targeting the RNA Component of Telomerase in Human Melanoma Cells journal February 2000
Structural and numerical chromosome changes in colon cancer develop through telomere-mediated anaphase bridges, not through mitotic multipolarity journal April 2005
The telomerase reverse transcriptase regulates chromatin state and DNA damage responses journal May 2005
Genes and pathways downstream of telomerase in melanoma metastasis journal July 2006
Telomerase inhibitors based on quadruplex ligands selected by a fluorescence assay journal March 2001
Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity journal April 2000
Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation journal April 2001
Essential role for Cdk2 inhibitory phosphorylation during replication stress revealed by a human Cdk2 knockin mutation journal May 2013
Telomerase contributes to tumorigenesis by a telomere length-independent mechanism journal August 2002
Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging journal October 2001
Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors journal October 2001
Genistein, a dietary-derived inhibitor of in vitro angiogenesis. journal April 1993
A biomarker that identifies senescent human cells in culture and in aging skin in vivo. journal September 1995
Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts journal November 1996
Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb journal September 1997
Inhibition of human telomerase by 2'-O-methyl-RNA journal September 1998
Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization journal December 1998
Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death journal December 1999
Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening journal March 1999
Chromosomal instability and cytoskeletal defects in oral cancer cells journal January 2000
BRG-1 is required for RB-mediated cell cycle arrest journal July 2000
Nuclear Targeting of 6-Phosphofructo-2-kinase (PFKFB3) Increases Proliferation via Cyclin-dependent Kinases journal September 2009
Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype* journal October 2011
Human Telomerase Reverse Transcriptase (hTERT) Is a Novel Target of the Wnt/β-Catenin Pathway in Human Cancer journal September 2012
Novel Pathways Associated with Bypassing Cellular Senescence in Human Prostate Epithelial Cells journal April 2002
Mechanism of Human Telomerase Inhibition by BIBR1532, a Synthetic, Non-nucleosidic Drug Candidate journal May 2002
Identification of Target Genes of the p16INK4A-pRB-E2F Pathway journal November 2003
Secretion of Vascular Endothelial Growth Factor by Primary Human Fibroblasts at Senescence journal October 2006
Protective Effects of Mastic Oil From Pistacia Lentiscus Variation Chia Against Experimental Growth of Lewis Lung Carcinoma journal September 2009
Efficacy and Safety of Short-Term Genistein Intervention in Patients with Localized Prostate Cancer Prior to Radical Prostatectomy: A Randomized, Placebo-Controlled, Double-Blind Phase 2 Clinical Trial journal August 2011
Critical requirement for cell cycle inhibitors in sustaining nonproliferative states journal March 2007
Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2 journal August 2010
Four faces of cellular senescence journal February 2011
Regulated expression of telomerase activity in human T lymphocyte development and activation. journal June 1996
Ginger Extract Inhibits Human Telomerase Reverse Transcriptase and c-Myc Expression in A549 Lung Cancer Cells journal December 2010
Transcriptional Silencing of a Novel hTERT Reporter Locus during In Vitro Differentiation of Mouse Embryonic Stem Cells journal February 2007
Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells journal January 2007
Physiologically achievable concentrations of genistein enhance telomerase activity in prostate cancer cells via the activation of STAT3 journal July 2007
Decreased 7,12-dimethylbenz[a]anthracene-induced carcinogenesis coincides with the induction of antitumor immunities in adult female B6C3F1 mice pretreated with genistein journal September 2007
PPP1CA contributes to the senescence program induced by oncogenic Ras journal October 2007
The PI3K–Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability journal June 2010
Indole-3-carbinol downregulation of telomerase gene expression requires the inhibition of estrogen receptor-alpha and Sp1 transcription factor interactions within the hTERT promoter and mediates the G1 cell cycle arrest of human breast cancer cells journal June 2011
Immune surveillance of senescent cells--biological significance in cancer- and non-cancer pathologies journal April 2012
Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2 journal October 2012
Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor journal July 2013
Perillyl Alcohol Protects against Fe-NTA-Induced Nephrotoxicity and Early Tumor Promotional Events in Rat Experimental Model journal January 2007
A highly selective telomerase inhibitor limiting human cancer cell proliferation journal December 2001
Reversal of human cellular senescence: roles of the p53 and p16 pathways journal August 2003
Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression journal March 2013
Polyphenols, Inflammatory Response, and Cancer Prevention: Chlorination of Isoflavones by Human Neutrophils journal November 2003
Therapy-Induced Senescence in Cancer journal October 2010
Extensive Telomere Erosion in the Initiation of Colorectal Adenomas and Its Association With Chromosomal Instability journal August 2013
The role of DNA damage repair in aging of adult stem cells journal November 2007
G-quadruplex preferentially forms at the very 3′ end of vertebrate telomeric DNA journal December 2007
Antisense telomerase treatment: induction of two distinct pathways, apoptosis and differentiation journal July 1998
A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis journal November 2010
Genistein Inhibits Nonoxidative Ribose Synthesis in MIA Pancreatic Adenocarcinoma Cells: A New Mechanism of Controlling Tumor Growth journal January 2001
Chromosomal imbalances in primary and metastatic melanomas: over-representation of essential telomerase genes journal January 2003
3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway journal January 2014
LY294002 and Metformin Cooperatively Enhance the Inhibition of Growth and the Induction of Apoptosis of Ovarian Cancer Cells journal January 2012
Oncogene-induced Cellular Senescence journal January 2010
Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression journal January 2003
Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation journal June 2004
Myc activates telomerase journal June 1998
CDK inhibitors: positive and negative regulators of G1-phase progression journal June 1999
Telomere shortening and apoptosis in telomerase-inhibited human tumor cells journal September 1999
Shelterin: the protein complex that shapes and safeguards human telomeres journal September 2005
A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin journal June 2004
DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. journal November 1994
Implications of Cellular Senescence in Tissue Damage Response, Tumor Suppression, and Stem Cell Biology journal January 2008
Green Tea Compound in Chemoprevention of Cervical Cancer journal January 2010
Epithelial‐mesenchymal transition during invasion of cutaneous squamous cell carcinoma is paralleled by AKT activation journal October 2014
The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways journal July 2013
Co-Regulation of p16INK4a and Migratory Genes in Culture Conditions that Lead to Premature Senescence in Human Keratinocytes journal September 2005
Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells journal June 2008
Oxidative stress causes telomere damage in Fanconi anaemia cells – a possible predisposition for malignant transformation journal July 2008
Telomerase reverse transcriptase gene amplification in hepatocellular carcinoma journal November 2004
Genistein induces cell growth inhibition in prostate cancer through the suppression of telomerase activity journal January 2005
p16 INK4A is a robust in vivo biomarker of cellular aging in human skin journal October 2006
Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells: Oncogenes induce atypical senescence phenotype journal September 2011
Roscovitine blocks leukocyte extravasation by inhibition of cyclin-dependent kinases 5 and 9: Roscovitine blocks leukocyte extravasation journal June 2011
Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney journal February 2004
Targeting the telomere and shelterin complex for cancer therapy: current views and future perspectives journal February 2011
Regulatory mechanisms of interleukin-8 production induced by tumour necrosis factor-α in human hepatocellular carcinoma cells journal February 2012
Pharmaceutical regulation of telomerase and its clinical potential journal December 2011
Cellular senescence: a double-edged sword in the fight against cancer: Cellular senescence journal May 2012
Antiproliferative effect of rapamycin on human T-cell leukemia cell line Jurkat by cell cycle arrest and telomerase inhibition journal April 2008
Roscovitine Triggers Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells with Similar Efficiency as Combinations of Conventional Purine Analogs with Cyclophosphamide journal August 2009
Antitumor and Antiangiogenic Activity of Soy Phytoestrogen on 7,12-Dimethylbenz[α]anthracene-Induced Mammary Tumors Following Ovariectomy in Sprague-Dawley Rats journal September 2009
Perillyl Alcohol Is an Angiogenesis Inhibitor journal June 2004
Pharmacodynamics of the G-Quadruplex-Stabilizing Telomerase Inhibitor 3,11-Difluoro-6,8,13-trimethyl-8 H -quino[4,3,2- kl ]acridinium methosulfate (RHPS4) in Vitro: Activity in Human Tumor Cells Correlates with Telomere Length and Can Be Enhanced, or Antagonized, with Cytotoxic Agents journal September 2005
Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways journal March 2007
Potent Inhibition of Telomerase by Small-Molecule Pentacyclic Acridines Capable of Interacting with G-Quadruplexes journal November 2001
A G-Quadruplex-Interactive Potent Small-Molecule Inhibitor of Telomerase Exhibiting in Vitro and in Vivo Antitumor Activity journal May 2002
Heterochromatin and Epigenetic Control of Gene Expression journal August 2003
Cellular Senescence in Aging Primates journal March 2006
Protein Composition of Catalytically Active Human Telomerase from Immortal Cells journal March 2007
A Human Telomerase Holoenzyme Protein Required for Cajal Body Localization and Telomere Synthesis journal January 2009
Wnt/ -Catenin Signaling Regulates Telomerase in Stem Cells and Cancer Cells journal June 2012
Highly Recurrent TERT Promoter Mutations in Human Melanoma journal January 2013
TERT Promoter Mutations in Familial and Sporadic Melanoma journal January 2013
Functional evidence for an RNA template in telomerase journal February 1990
A Mammalian Telomerase-Associated Protein journal February 1997
Reverse Transcriptase Motifs in the Catalytic Subunit of Telomerase journal April 1997
Bypass of Senescence After Disruption of p21CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts journal August 1997
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells journal January 1998
Tankyrase, a Poly(ADP-Ribose) Polymerase at Human Telomeres journal November 1998
The RNA component of human telomerase journal September 1995
Functional characterization and developmental regulation of mouse telomerase RNA journal September 1995
Specific association of human telomerase activity with immortal cells and cancer journal December 1994
Definition of pRB- and p53-Dependent and -Independent Steps in HIRA/ASF1a-Mediated Formation of Senescence-Associated Heterochromatin Foci journal January 2007
Molecular Dissection of Formation of Senescence-Associated Heterochromatin Foci journal January 2007
Differential Roles for Cyclin-Dependent Kinase Inhibitors p21 and p16 in the Mechanisms of Senescence and Differentiation in Human Fibroblasts journal March 1999
Stress Signals Utilize Multiple Pathways To Stabilize p53 journal May 2000
Differential Regulation of Retinoblastoma Tumor Suppressor Protein by G 1 Cyclin-Dependent Kinase Complexes In Vivo journal July 2001
Expression of Telomerase RNA Template, but Not Telomerase Reverse Transcriptase, Is Limiting for Telomere Length Maintenance In Vivo journal August 2004
p53-Dependent Transcriptional Repression of c-myc Is Required for G 1 Cell Cycle Arrest journal September 2005
Deregulated E2F Activity Induces Hyperplasia and Senescence-Like Features in the Mouse Pituitary Gland journal April 2005
Primary and Compensatory Roles for RB Family Members at Cell Cycle Gene Promoters That Are Deacetylated and Downregulated in Doxorubicin-Induced Senescence of Breast Cancer Cells journal April 2006
The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression journal January 2010
Inhibition of CDKS by roscovitine suppressed LPS-induced · NO production through inhibiting NFκB activation and BH 4 biosynthesis in macrophages journal September 2009
Rapid Inhibition of Cancer Cell Growth Induced by Lentiviral Delivery and Expression of Mutant-Template Telomerase RNA and Anti-telomerase Short-Interfering RNA journal July 2004
Escape from Therapy-Induced Accelerated Cellular Senescence in p53-Null Lung Cancer Cells and in Human Lung Cancers journal April 2005
Chemoprevention of Human Prostate Cancer by Oral Administration of Green Tea Catechins in Volunteers with High-Grade Prostate Intraepithelial Neoplasia: A Preliminary Report from a One-Year Proof-of-Principle Study journal January 2006
In vivo Inhibition of Lung Cancer by GRN163L: A Novel Human Telomerase Inhibitor journal September 2005
Lack of Telomerase Gene Expression in Alternative Lengthening of Telomere Cells Is Associated with Chromatin Remodeling of the hTR and hTERT Gene Promoters journal September 2005
The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation through Paracrine Mechanisms journal January 2006
Transcriptional Repression of Telomerase RNA Gene Expression by c-Jun-NH 2 -Kinase and Sp1/Sp3 journal February 2006
Genistein Represses Telomerase Activity via Both Transcriptional and Posttranslational Mechanisms in Human Prostate Cancer Cells journal February 2006
Cyclin-Dependent Kinase 5 Activity Controls Cell Motility and Metastatic Potential of Prostate Cancer Cells journal August 2006
Targeting Multiple Signaling Pathways by Green Tea Polyphenol (−)-Epigallocatechin-3-Gallate journal March 2006
Oncogene-Induced Senescence: Putting the Brakes on Tumor Development: Figure 1. journal March 2006
Induction of Senescence in Diterpene Ester–Treated Melanoma Cells via Protein Kinase C–Dependent Hyperactivation of the Mitogen-Activated Protein Kinase Pathway journal October 2006
Agonist and Antagonist of Retinoic Acid Receptors Cause Similar Changes in Gene Expression and Induce Senescence-like Growth Arrest in MCF-7 Breast Carcinoma Cells journal September 2006
Telomere-Driven Karyotypic Complexity Concurs with p16 INK4a Inactivation in TP53 -Competent Immortal Endothelial Cells journal November 2006
Antiadhesive Effects of GRN163L—An Oligonucleotide N3′→P5′ Thio -Phosphoramidate Targeting Telomerase journal February 2007
Epigallocatechin-3-Gallate Enhances CD8 + T Cell–Mediated Antitumor Immunity Induced by DNA Vaccination journal January 2007
Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion journal April 2007
Genistein Induces the p21WAF1/CIP1 and p16INK4a Tumor Suppressor Genes in Prostate Cancer Cells by Epigenetic Mechanisms Involving Active Chromatin Modification journal April 2008
Curcumin Disrupts the Mammalian Target of Rapamycin-Raptor Complex journal January 2009
Senescence-Associated Oxidative DNA Damage Promotes the Generation of Neoplastic Cells journal October 2009
Identification of a Biphasic Role for Genistein in the Regulation of Prostate Cancer Growth and Metastasis journal April 2009
Clinical Pharmacology of Resveratrol and Its Metabolites in Colorectal Cancer Patients journal September 2010
PPARδ Induces Estrogen Receptor-Positive Mammary Neoplasia through an Inflammatory and Metabolic Phenotype Linked to mTOR Activation journal June 2013
Foxp3 + T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition journal February 2014
Telomerase Template Antagonist GRN163L Disrupts Telomere Maintenance, Tumor Growth, and Metastasis of Breast Cancer journal May 2006
Telomerase Inhibition and Cell Growth Arrest After Telomestatin Treatment in Multiple Myeloma journal January 2004
Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer journal July 2008
Curcumin Inhibits Prosurvival Pathways in Chronic Lymphocytic Leukemia B Cells and May Overcome Their Stromal Protection in Combination with EGCG journal February 2009
Expression of p16 and Retinoblastoma Determines Response to CDK4/6 Inhibition in Ovarian Cancer journal January 2011
Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma journal September 2013
Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells journal May 2006
Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy journal April 2008
Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis journal July 2008
Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor journal March 2011
The Cyclin-Dependent Kinase Inhibitor SCH 727965 (Dinacliclib) Induces the Apoptosis of Osteosarcoma Cells journal April 2011
Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas journal August 2012
Cdk4/6 Inhibition Induces Epithelial–Mesenchymal Transition and Enhances Invasiveness in Pancreatic Cancer Cells journal August 2012
Ligand Binding Promotes CDK-Dependent Phosphorylation of ER-Alpha on Hinge Serine 294 but Inhibits Ligand-Independent Phosphorylation of Serine 305 journal June 2012
Inhibition of mTOR Pathway Sensitizes Acute Myeloid Leukemia Cells to Aurora Inhibitors by Suppression of Glycolytic Metabolism journal September 2013
Interleukin-6 and Oncostatin-M Synergize with the PI3K/AKT Pathway to Promote Aggressive Prostate Malignancy in Mouse and Human Tissues journal July 2013
Tea Polyphenols Decrease Serum Levels of Prostate-Specific Antigen, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor in Prostate Cancer Patients and Inhibit Production of Hepatocyte Growth Factor and Vascular Endothelial Growth Factor In vitro journal June 2009
Differential Inhibition of Protein Translation Machinery by Curcumin in Normal, Immortalized, and Malignant Oral Epithelial Cells journal February 2010
A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer journal January 2010
Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia journal March 2011
Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells journal April 2011
A Novel Prodrug of Epigallocatechin-3-gallate: Differential Epigenetic hTERT Repression in Human Breast Cancer Cells journal March 2011
Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice journal December 2011
Curcumin-Targeting Pericellular Serine Protease Matriptase Role in Suppression of Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis journal March 2013
The mTORC1 Inhibitor Everolimus Prevents and Treats Eμ- Myc Lymphoma by Restoring Oncogene-Induced Senescence journal December 2012
In vitro Induction of Apoptosis in U937 Cells by Perillyl Alcohol with Sensitization by Pentoxifylline: Increased BCL-2 and BAX Protein Expression journal January 2006
Arsenic inhibition of telomerase transcription leads to genetic instability journal November 2001
Telomeres, stem cells, senescence, and cancer journal January 2004
Ink4a/Arf expression is a biomarker of aging journal November 2004
The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer journal January 2007
Nanog signaling in cancer promotes stem-like phenotype and immune evasion journal October 2012
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities journal March 2013
Curcumin Inhibits Skin Squamous Cell Carcinoma Tumor Growth In Vivo journal March 2011
A High-Throughput Method to Identify Novel Senescence-Inducing Compounds journal July 2009
Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention journal July 2004
Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma journal January 2004
Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532 journal February 2005
Frequency of telomerase-specific CD8+ T lymphocytes in patients with cancer journal February 2006
Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity journal September 2006
Telomerase Regulation, Cell Cycle, and Telomere Stability in Primitive Hematopoietic Cells journal July 1997
Different fatty acid metabolism effects of (−)-Epigallocatechin-3-Gallate and C75 in Adenocarcinoma lung cancer journal July 2012
MDM2 negatively regulates the human telomerase RNA gene promoter journal January 2005
Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma Cells journal November 2007
Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells journal January 2012
Telomerase inhibition by siRNA causes senescence and apoptosis in Barrett's adenocarcinoma cells: mechanism and therapeutic potential journal January 2005
Telomerase immunity from bench to bedside: round one journal February 2007
Elevated expression of CDK4 in lung cancer journal January 2011
Overexpression of PTEN suppresses lipopolysaccharide-induced lung fibroblast proliferation, differentiation and collagen secretion through inhibition of the PI3-K-Akt-GSK3beta pathway journal January 2014
Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma journal January 2013
PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro journal October 2009
Phase I Trial of Daily Oral Polyphenon E in Patients With Asymptomatic Rai Stage 0 to II Chronic Lymphocytic Leukemia journal August 2009
Inactivation of AKT Induces Cellular Senescence in Uterine Leiomyoma journal April 2014
Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation journal January 2005
DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion journal November 2010
Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor journal December 2008
Dynamic Telomerase Gene Suppression via Network Effects of GSK3 Inhibition journal July 2009
A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen journal February 2010
Exploring the Gain of Function Contribution of AKT to Mammary Tumorigenesis in Mouse Models journal February 2010
Genistein Increases Epidermal Growth Factor Receptor Signaling and Promotes Tumor Progression in Advanced Human Prostate Cancer journal May 2011
EGCG Enhances the Therapeutic Potential of Gemcitabine and CP690550 by Inhibiting STAT3 Signaling Pathway in Human Pancreatic Cancer journal February 2012
Expression of Constitutively Active CDK1 Stabilizes APC-Cdh1 Substrates and Potentiates Premature Spindle Assembly and Checkpoint Function in G1 Cells journal March 2012
Longitudinal Imaging Studies of Tumor Microenvironment in Mice Treated with the mTOR Inhibitor Rapamycin journal November 2012
Epigenetic Regulation of Multiple Tumor-Related Genes Leads to Suppression of Breast Tumorigenesis by Dietary Genistein journal January 2013
Metabolomics Reveals Metabolic Targets and Biphasic Responses in Breast Cancer Cells Treated by Curcumin Alone and in Association with Docetaxel journal March 2013
Genistein Up-Regulates Tumor Suppressor MicroRNA-574-3p in Prostate Cancer journal March 2013
The Anti-Melanoma Activity of Dinaciclib, a Cyclin-Dependent Kinase Inhibitor, Is Dependent on p53 Signaling journal March 2013
Conditional Transgenic Expression of PIM1 Kinase in Prostate Induces Inflammation-Dependent Neoplasia journal April 2013
Cancer-Associated Fibroblasts Promote Proliferation of Endometrial Cancer Cells journal July 2013
CXCR2-Driven Ovarian Cancer Progression Involves Upregulation of Proinflammatory Chemokines by Potentiating NF-κB Activation via EGFR-Transactivated Akt Signaling journal December 2013
Epigallocatechin-3-Gallate Inhibits Photocarcinogenesis Through Inhibition of Angiogenic Factors and Activation of CD8+ T Cells in Tumors journal January 2005
The Identification of Senescence-Specific Genes during the Induction of Senescence in Prostate Cancer Cells journal September 2005
Targeting Protein Kinase C (PKC) and Telomerase by Phenethyl Isothiocyanate (PEITC) Sensitizes PC-3 Cells Towards Chemotherapeutic Drug-Induced Apoptosis journal January 2009
Low-Dose Exposure to γ Rays Induces Specific Gene Regulations in Normal Human Keratinocytes journal June 2005
IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ‘Bystander senescence’ journal December 2012
Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer journal April 2009
Targeting the Akt Kinase to Modulate Survival, Invasiveness and Drug Resistance of Cancer Cells journal April 2013
Inhibition of Akt/mTOR Signaling by the Dietary Flavonoid Fisetin journal July 2013
Binding interaction between (−)-epigallocatechin gallate causes impaired spreading of cancer cells on fibrinogen journal January 2013
Genotoxic Effects of Green Tea Extract on Human Laryngeal Carcinoma Cells In Vitro journal June 2011
Enhanced cytotoxicity of optimized liposomal genistein via specific induction of apoptosis in breast, ovarian and prostate carcinomas journal September 2013
Evidence for telomerase involvement in the angiogenesis of astrocytic tumors: expression of human telomerase reverse transcriptase messenger RNA by vascular endothelial cells journal June 2001
Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer journal September 1999
The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells journal July 2013
PI3K/AKT/mTOR Pathway in Angiogenesis journal January 2011
Treatment with EGCG in NSCLC leads to decreasing intersti-tial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2: Treatment with EGCG in NSCLC leads to decreasing intersti-tial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2 journal June 2013
Capecitabine combined with (-)-epigallocatechin-3-gallate inhibits angiogenesis and tumor growth in nude mice with gastric cancer xenografts journal January 2012
Imetelstat (a telomerase antagonist) exerts off-target effects on the cytoskeleton journal March 2013
Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells journal May 2013
Role of Ku70 and Bax in epigallocatechin-3-gallate-induced apoptosis of A549 cells in vivo journal October 2012
Telomerase reverse transcriptase promotes the proliferation of human laryngeal carcinoma cells through activation of the activator protein 1 journal May 2013
Silencing of the hTERT gene through RNA interference induces apoptosis via Bax/Bcl-2 in human glioma cells journal August 2012
Overexpression of human telomerase reverse transcriptase promotes the motility and invasiveness of HepG2 cells in vitro journal June 2013
Genistein attenuates cancer stem cell characteristics in gastric cancer through the downregulation of Gli1 journal December 2013
(−)-Epigallocatechin-3-gallate suppresses liver metastasis of human colorectal cancer journal December 2013
Active form of AKT controls cell proliferation and response to apoptosis in hepatocellular carcinoma journal December 2013
Epigallocatechin gallate inhibits the growth of human lung cancer by directly targeting the EGFR signaling pathway journal December 2013
Upregulation of estrogen receptor mediates migration, invasion and proliferation of endometrial carcinoma cells by regulating the PI3K/AKT/mTOR pathway journal December 2013
MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis journal March 2011
Ex Vivo Characterization of Multiepitopic Tumor-Specific CD8 T Cells in Patients with Chronic Myeloid Leukemia: Implications for Vaccine Development and Adoptive Cellular Immunotherapy journal June 2005
Cutting Edge: T Cell Development Requires the Combined Activities of the p110γ and p110δ Catalytic Isoforms of Phosphatidylinositol 3-Kinase journal August 2005
Curcumin sensitizes chemotherapeutic drugs via modulation of PKC, telomerase, NF-κB and HDAC in breast cancer journal October 2011
Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models journal October 2011
A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS journal July 2013
Curcumin suppresses proliferation and invasion in human gastric cancer cells by down-regulation of PAK1 activity and cyclin D1 expression journal July 2009
Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer journal January 2010
The specific role of pRb in p16 INK4A -mediated arrest of normal and malignant human breast cells journal March 2012
Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis, via glycolysis and ketone production journal June 2012
CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy journal January 2012
Human telomerase reverse transcriptase (hTERT) is a target gene of β-catenin in human colorectal tumors journal September 2012
A high-content cellular senescence screen identifies candidate tumor suppressors, including EPHA3 journal February 2013
CDK4 inhibition restores G₁-S arrest in MYCN - amplified neuroblastoma cells in the context of doxorubicin-induced DNA damage journal April 2013
Induction of prolonged early G 1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1 journal June 2013
Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR) journal September 2013
CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth journal December 2013
Role of Rb Family in the Epigenetic Definition of Chromatin journal April 2005
Telomerase activation by c-Myc in human mammary epithelial cells requires additional genomic changes journal October 2009
Increased angiogenesis in Cdk4 R24C/R24C :Apc +/Min intestinal tumors journal June 2010
Cancer-Associated Fibroblasts Promote Proliferation of Endometrial Cancer Cells image January 2019
Cancer-Associated Fibroblasts Promote Proliferation of Endometrial Cancer Cells image January 2019
CDK5 and Its Activator P35 in Normal Pituitary and in Pituitary Adenomas: Relationship to VEGF Expression journal January 2014

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Premature aging/senescence in cancer cells facing therapy: good or bad? journal September 2015
P53-dependent downregulation of hTERT protein expression and telomerase activity induces senescence in lung cancer cells as a result of pterostilbene treatment journal August 2017
New prospects for targeting telomerase beyond the telomere journal June 2016
ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases journal January 2016
Biological and toxicological evaluation of Rhus trilobata Nutt. (Anacardiaceae) used traditionally in mexico against cancer journal July 2019
Recent advances in managing/understanding meningioma journal January 2018
Epstein–Barr Virus in Gliomas: Cause, Association, or Artifact? journal April 2018
p53 Isoforms and Their Implications in Cancer journal August 2018
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Related Subjects

60 APPLIED LIFE SCIENCES
Oncogenic stress
Oncology
Senescence
Telomerase
p53
pRB