Location of Repository

Characterisation of TRAIL Receptor Signalling To Apoptosis in Pre-clinical Models of Breast Cancer

By Shambhavi Naik

Abstract

TNF-Related Apoptosis-Inducing Ligand (TRAIL) belongs to the TNF cytokine family\ud and can signal to apoptosis by binding to either of two membrane-bound death\ud receptors, TRAIL-R1 or TRAIL-R2. Using ligands specific for TRAIL-R1 (R1L) or\ud TRAIL-R2 (R2L), our laboratory has previously shown that combining a histone\ud deacetylase inhibitor with R1L, but not R2L, induces apoptosis in primary chronic\ud lymphocytic leukaemia cells. The aim of this project was to extend the profiling of\ud TRAIL-Receptor signalling to breast cancer, using breast cancer cell lines and\ud importantly primary breast tumours as model systems.\ud A 3-dimensional explant culturing technique was employed to maintain the primary\ud tumour architecture and mimic the breast tumour microenvironment. In addition,\ud tumour-initiating cells from advanced metastatic breast cancer patients were also\ud tested for their sensitivity to TRAIL. The results obtained from breast cancer cell lines,\ud primary mucinous carcinomas and advanced metastatic breast cancer cells suggest\ud that in breast cancer, TRAIL-R1 is the predominant functional TRAIL death receptor\ud independent of oestrogen receptor status. In contrast, invasive ductal/lobular\ud carcinomas (IDC/ILC) were resistant to TRAIL-induced apoptosis and required the\ud breast cancer chemotherapeutic, doxorubicin as a sensitising agent. Studies using the\ud TRAIL-resistant cell line, T47D, demonstrated that doxorubicin sensitised tumour cells\ud to TRAIL-induced apoptosis via enhanced TRAIL DISC formation. Importantly, in\ud primary tumour explants, the combination of doxorubicin and TRAIL signalled to\ud apoptosis exclusively in the tumour cells, but not in normal cells. Significantly, in four\ud IDC/ILC tumours, doxorubicin sensitised breast tumour cells to R1L more efficiently\ud than R2L. Therefore, using R1L in combination with sub-lethal doses of\ud chemotherapeutic agents could improve the benefit of conventional therapy whilst\ud reducing drug-associated side-effects and potential TRAIL-mediated cell\ud proliferation/survival in apoptosis-resistant tumour cells. My data suggest that using a\ud TRAIL-R1-selective agonist with an appropriate sensitising agent (example,\ud doxorubicin), offers a promising therapeutic approach for treatment of breast cancer

Publisher: University of Leicester
Year: 2011
OAI identifier: oai:lra.le.ac.uk:2381/9913

Suggested articles

Preview

Citations

  1. (2005b) TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies.
  2. (2006). A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.
  3. (1999). A critical evaluation of the mechanisms of action proposed for the antitumour effects of the anthracycline antibiotics adriamycin and daunorubicin.
  4. (2004). A multigene assay to predict recurrence of tamoxifen-treated nodenegative breast cancer.
  5. (1997). A novel receptor for Apo2L/TRAIL contains a truncated death domain.
  6. (2010). A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combinatin with 5-fluorouracil and leucovorin in patients with refractory solid tumours.
  7. (1976). A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding.
  8. (1998). A simple method of tumour culture.
  9. (1998). A single BIR domain of XIAP sufficient for inhibiting caspases.
  10. (2007). A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling.
  11. (2005). A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells.
  12. (2008). ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis.
  13. (2010). Acquired resistance to ABT737 in lymphoma cells that up-regulate MCL-1 and BFL-1.
  14. (2006). Acquired TRAIL resistance in human breast cancer cells are caused by the sustained cFLIP(L) and XIAP protein levels and ERK activation.
  15. (1996). Activation of apoptosis by Apo-2 ligand is independent of FADD but bloxked by CrmA.
  16. (2010). Activation of the Akt survival pathway contributes to TRAIL resistance in cancer cells.
  17. (2000). Active caspases and cleaved cytokeratins are sequestered into cytoplasmic inclusions in TRAIL-induced apoptosis.
  18. (1984). Adriamycininduced DNA damage mediated by mammalian DNA topoisomerase II.
  19. (2008). AKT1(E17K) in human solid tumours.
  20. (1998). Altered mucin expression is a field change that accompanies mucinous (colloid) breast carcinoma histogenesis.
  21. (1997). An Antagonist Decoy Receptor and a Death Domain-Containing Receptor for TRAIL.
  22. (2003). An antibody against DR4 (TRAIL-R1) in combination with doxorubicin selectively kills malignant but not normal prostate cells.
  23. (1998). An Induced Proximity Model for Caspase-8 Activation.
  24. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
  25. (2001). Anoikis mechanisms.
  26. (2010). Anti-HER2 neoadjuvant and adjuvant therapies in HER2 positive breast cancer.
  27. (2003). Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model.
  28. (2001). Apo2L/TRAIL and Bcl-2-related proteins regulate Type I interferoninduced apoptosis in multiple myeloma.
  29. (2009). Apomab, a fully human agonistic antibody to DR5, exhibits potent antitumour activity against primary and metastatic breast cancer.
  30. (1995). Apoptosis in the pathogenesis and treatment of disease.
  31. (2000). Apoptosis induced in normal human hepatocytes by tumor necrosis factorrelated apoptosis-inducing ligand.
  32. (2008). Apoptosis resistance in epithelial tumors is mediated by tumor-cellderived interleukin-4.
  33. (2007). Autocrine TNFα signalling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis.
  34. (2002). beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.
  35. (2008). BH3-mimetic ABT-737 potentiates TRAILmediated apoptotic signalling by unsequestering Bim and Bak in human pancreatic cells.
  36. (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
  37. (1996). BID: a novel BH3 domain-only death agonist.
  38. (2010). Bortezomib sensitizes primary human esthesioneuroblastoma cells to TRAIL-induced apopotsis.
  39. (2003). Breast cancer cell lines: friend or foe? Breast Cancer Res.
  40. (2005). c-FLIPR, a new regulator of death receptor-induced apoptosis.
  41. (2005). Cancer Trialists' Collaborative Group (EBCTCG)
  42. (2001). Caspase-10 is an initiator caspase in death receptor signaling.
  43. (2002). Caspase-10 is recruited to and activated at the native TRAIL and CD95 deathinducing signalling complexes in a FADD-dependent manner but cannot functionally substitute caspase-8.
  44. (2005). Caspase-10 sensitizes breast carcinoma cells to TRAIL-induced but not tumour necrossi factor-induced apoptosis in a caspase-3 dependent manner.
  45. (1998). Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis.
  46. (2005). Caspase-independent cell death.
  47. (1997). Caspases: the executioners of apoptosis.
  48. (2011). Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis.
  49. (1998). Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex.
  50. (1980). Cell Death: The Significance of Apoptosis.
  51. (2001). Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex.
  52. (2005). Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury.
  53. (1999). Chemotherapy Augments TRAIL-Induced Apoptosis in Breast Cell Lines.
  54. (2003). Chemotherapy enhances TNF-related apoptosisinducing ligand DISC assembly in HT29 human colon cancer cells.
  55. (2005). Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1.
  56. (2009). Classification of cell death: recommendations of the Nomenclature Committee on Cell Death
  57. (1999). Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.
  58. (1997). Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family.
  59. (2003). Combination of TRAIL gene therapy and chemotherapy enhances antitumor and antimetastasis effects in chemosensitive and chemoresistant breast cancers.
  60. (2008). Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist.
  61. (2000). Combined effect of tumour necrosis factorrelated apoptosis-inducing ligand and ionising radiation in breast cancer therapy.
  62. (2009). Conjugation of doxorubicin to cell penetrating peptides sensitizes human breast MDAMB-231 cancer cells to endogenous TRAIL-induced apoptosis.
  63. (1997). Control of TRAIL-induced apoptosis by a family of signalling and decoy receptors.
  64. (2006). Converting a breast cancer microarray signature into a high throughput diagnostic test.
  65. (1984). Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer.
  66. (2009). Cullin-3 based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling.
  67. (2005). Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5).
  68. (2000). Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL.
  69. (1997). Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade.
  70. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor.
  71. (2004). Death receptor 4 (DR4) efficiently kills breast cancer cells irrespective of their sensitivity to tumor necrosis factor-related apoptosisinducing ligand (TRAIL).
  72. (2001). Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8.
  73. (2005). Death to the bad guys, targeting cancer via Apo2L/TRAIL. Apoptosis
  74. (2007). Death-receptor O-glycosylation controls tumour cell-sensitivity to the pro-apoptotic ligand Apo2L/TRAIL.
  75. (2003). Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL/- mice.
  76. (2001). Differential activation of TRAIL-R1 and -R2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative.
  77. (1999). Differential effects of chemotherapeutic agents on the Bcl-2/Bax apoptosis pathway in human breast cancer cell line MCF-7.
  78. (1987). Differential formation of hydroxyl radicals by adriamycin in sensitive and resistant MCF-7 human breast tumour cells.
  79. (2001). Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions.
  80. (2006). Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2.
  81. (2000). Differential localisation and regulation of death and decoy receptors for TNF-Related ApoptosisInducing Ligand (TRAIL) in human melanoma cells.
  82. (2004). Differential regulation of the TRAIL death receptors DR4 and DR5 by the signal recognition particle.
  83. (2008). Differential responsiveness to human hepatocytes to TRAIL in combination with either histone deacetylase inhibitors or conventional cytostatics.
  84. (2004). Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.
  85. (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.
  86. (1999). Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis.
  87. (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139.
  88. (2002). Downregulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance.
  89. (2010). Doxorubicin and etoposide sensitize small cell lung carcinoma cells expressing caspase-8 to TRAIL.
  90. (2007). Doxorubicin enhances TRAIL-induced cell death via ceramide-enriched membrane platforms.
  91. (2005). Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts.
  92. (2002). Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression.
  93. (2002). E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer?
  94. (1997). E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis.
  95. (1995). E-cadherin is a tumour/invasion suppressor gene mutated in lobular breast cancers.
  96. (1996). E-cadherin is inactivated in a majority of invasive human lobular cancers by truncation mutations throughout its extracellular domain.
  97. (1976). Effect of adriamycin on DNA, RNA and protein synthesis in cell-free systems and intact cells.
  98. (2005). Effects of sequential treatments with chemotherapeutic drugs followed by TRAIL on prostate cancer in vitro and in vivo.
  99. (2004). Enhanced caspase-8 recruitment to and activation of the DISC is critical for sensitization of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs.
  100. (2009). Enhanced Fas-Associated Death Domain recruitment by histone deacetylase inhibitors is critical for the sensitization of chronic lymphocytic leukemia cells to TRAIL-induced apoptosis.
  101. (1977). Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer.
  102. (2001). Estrogen Receptors: orchestrators of pleiotropic cellular responses.
  103. (2005). Evaluating the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in breast cancer.
  104. (2001). Evidence that the death receptor DR4 is a DNA damage-inducible, p53 regulated gene.
  105. (1999). Expression and Function of TNF-Related Apoptosis-Inducing Ligand on Murine Activated NK cells.
  106. (2000). Expression of the apoptosis-inducing ligands FasL and TRAIL in malignant and benign human breast tumors.
  107. (2000). FADD is required for DR4-and DR5-mediated apoptosis: lack of TRAIL-induced apoptosis in FADD-deficient mouse embryonic fibroblasts.
  108. (1995). FADD, a Novel Death Domain-Containing Protein, Interacts with the Death Domain of Fas and Initiates Apoptosis.
  109. (2000). FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2.
  110. (2000). Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule.
  111. (2006). Fibroblasts in cancer.
  112. (2007). Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.
  113. (2006). Flavopiridol induces cellular FLICE-inhibitory protein degradation by the proteosome and promotes TRAIL-induced early signalling and apoptosis in breast tumour cells.
  114. (1996). Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells.
  115. (2007). Flavopiridol synergizes TRAIL cytotoxicity by down regulation of FLIPL.
  116. (1999). Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials.
  117. (1997). FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b.
  118. (2011). Functional complementation between FADD and RIP1 in embryos and lymphocytes.
  119. (2009). General and Systematic Pathology: Fifth edition,
  120. (2009). Genes that mediate breast cancer metastasis to the brain.
  121. (1996). Growth arrest and non-apoptotic cell death associated with the suppression of c-myc expression in MCF7 breast tumour cells following acute exposure to doxorubicin.
  122. (1992). Growth inhibition with reversible cell cycle arrest of carcinoma cells by Flavone L86-8275.
  123. (2011). Hallmarks of cancer: The next generation.
  124. (2005). HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma.
  125. (1992). Helicase inhibition by anthracycline anticancer agents.
  126. (2005). HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo.
  127. (2004). Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies.
  128. (2002). HSP70 protects against TNF-induced lethal inflammatory shock.
  129. (1994). Hypoxia and drug resistance.
  130. (2007). IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation and TNFα-dependent apoptosis.
  131. (2007). IAP antagonists target cIAP1 to degradation to induce TNFα-dependent apoptosis.
  132. (1995). Identification and characterization of a new member of the TNF family that induces apoptosis.
  133. (1997). Identification and Molecular Cloning of Two Novel Receptors for the Cytotoxic Ligand TRAIL.
  134. (2008). Identification of an antiapoptotic protein complex at death receptors.
  135. (2000). Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins.
  136. (2008). Identification of RIP1 kinase as a specific cellular target of necrostatins.
  137. (2004). Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma.
  138. (2009). Immunohistochemical expression of PTEN and phosphorylated Akt are not correlated with clinical outcome in breast cancer patients treated with trastuzumabcontaining neo-adjuvant chemotherapy.
  139. (1981). Inactivation of aromatase in vitro by 4-hydroxy-4-androstene3,17-dione and 4-acetoxy-4-androstene-3, 17-dione and sustained effects in vivo.
  140. (2007). Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver.
  141. (2005). Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis.
  142. (2002). Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice.
  143. (1996). Induction of apoptosis by Apo-2 Ligand, a new member of the tumor necrosis cytokine family.
  144. (1998). Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor.
  145. (2007). Investigating the interaction between osteoprotegerin and receptor activator of NF-kappaBor tumour necrosis factor-related apoptosis-inducing ligand: evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways.
  146. (1997). KILLER/DR5 is a DNA damage-inducible p53-upregulated death receptor gene.
  147. (1997). Lethal effect of recombinant human Fas ligand in mice pretreated with Propionibacterium acnes.
  148. (1993). Lethal effects of the anti-Fas antibody in mice.
  149. (2002). Limited penetration of anticancer drugs through tumour tissue: a potential cause of resistance of solid tumours to chemotherapy.
  150. (1999). Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity.
  151. (2007). Low concentrations of doxorubicin sensitizes human solid cancer cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor R2-mediated apoptosis by inducing TRAILR2 expression.
  152. (1998). Lymphocyte inhibitor of TRAIL (TNF-related apoptosis-inducing ligand): a new receptor protecting lymphocytes from the death ligand TRAIL.
  153. (2009). Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a Phase I study.
  154. (2009). Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study.
  155. (2011). Mechanisms of endocrine resistance in breast cancer.
  156. (1995). Medullary carcinoma of the breast. Prevalence and prognostic importance of classical risk factors in breast cancer.
  157. (2004). Molecular basis of Breast Cancer. Chapter 2; The Breast as a Developing Organ;
  158. (2008). Molecular characterisation of the tumour microenvironment in breast cancer.
  159. (2005). Molecular classification and molecular forecasting of breast cancer: ready for clinical application?
  160. (2011). Molecular determinants of Smac mimetic induced degradation of cIAP1 and cIAP2. Cell Death Differ (Advanced online publication ahead of print;
  161. (2005). Molecular evolution of breast cancer.
  162. (2005). Molecular mechanisms of drug resistance.
  163. (2000). Molecular portraits of human breast tumours.
  164. (1999). Monocyte-mediated Tumoricidal Activity via the Tumor Necrosis Factorrelated Cytokine,
  165. (2002). Multidrug resistance in cancer: role of ATP-dependent transporters.
  166. (2010). Multifunctional nanoparticles delivering small interfering RNA and doxorubicin overcome drug resistance in cancer.
  167. (2001). Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast.
  168. (2002). Mutation analysis and mRNA expression of trail-receptors in human breast cancer.
  169. (2001). Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers.
  170. (2007). Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways.
  171. (2000). Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.
  172. (2004). Organization. The Global Burden of Disease:
  173. (1998). Osteoprotegerin is a receptor for the the cytotoxic ligand TRAIL.
  174. (2010). p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication.
  175. (1998). p53-dependent and -independent Regulation of the Death Receptor KILLER/DR5 Gene Expression in Response to Genotoxic Stress and Tumor Necrosis Factor α.
  176. (2009). Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling.
  177. (1992). Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up.
  178. (2004). Pathways of apoptotic and non-apoptotic death in tumour cells.
  179. (2007). Phase 1 and pharmacokinetic study of lexutumumab in patients with advanced cancers.
  180. (2010). Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors.
  181. (2006). Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer.
  182. (2007). Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1.
  183. (2011). Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small cell lung cancer and other solid tumours.
  184. (2010). Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer.
  185. (1986). Phenol red in tissue culture media is a weak estrogen: Implications concerning the study of estrogenresponsive cells in culture.
  186. (2008). Phosphatidylinositol 3-kinase inhibition broadly sensitizes gliobastoma cells to death receptor- and drug-induced apoptosis.
  187. (2008). PIK3CA cancer mutations display gender and tissue specificity patterns.Hum
  188. (2001). Potential and Caveats of TRAIL in cancer therapy.
  189. (2006). Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs.
  190. (2001). Preclinical studies to predict the disposition of Apo2L/tumor necrosis factorrelated apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety.
  191. (2005). Preligand assembly domain-mediated ligandindependent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAILinduced apoptosis.
  192. (2000). Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c.
  193. (2001). Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.
  194. (1997). Processing/Activation of at least four interleukin-1β converting enzyme-like proteases occurs during the execution phase of apoptosis in human monocytic tumour cells.
  195. (2009). Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer.
  196. (2003). Progressive resistance of BTK-143 osteosarcoma cells to Apo2L/TRAILinduced apoptosis is mediated by acquisition of DcR2/TRAIL-R4 expression: resensitisation with chemotherapy.
  197. (2009). Proteomic and molecular characterisation of TRAIL-induced signalling complexes.
  198. (2001). PUMA, a novel proapoptotic gene, is induced by p53.
  199. (2005). Receptor-selective Mutants of Apoptosisinducing Ligand 2/Tumor Necrosis Factor-related Apoptosis-inducing Ligand Reveal a Greater Contribution of Death Receptor (DR) 5 than DR4 to Apoptosis Signaling.
  200. (2008). Recombinant TRAIL and TRAIL receptor analysis.
  201. (2009). Reconstitution of the death-inducing signalling complex reveals a substrate switch that determines CD95-mediated death or survival.
  202. (2010). Regulation of breast cancer stem cell activity by signalling through the Notch4 receptor.
  203. (2010). Regulation of Myc by miR-34c: A mechanism to prevent genomic instability. Cell cycle 9,
  204. (2009). Repeated treatment with subtoxic doses of TRAIL induces resistance to apoptosis through its death receptors in MDA-MB-231 breast cancer cells.
  205. (1986). Resistance to adriamycin: relationship of cytotoxicity to drug uptake and DNA single- and double-strand breakage in cloned cell lines of adriamycin-sensitive and -resistant P388 leukemia.
  206. (2004). Resistance to TRAIL-induced apoptosis in ovarian cancer cell lines is overcome by co-treatment with cytotoxic drugs.
  207. (2001). Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumour-selective death ligand TRAIL.
  208. (2011). RIP3 mediates the embryonic lethality of caspase-8 deficient mice.
  209. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand.
  210. (2003). Selective and non-selective toxicity of TRAIL/Apo2L combined with chemotherapy in human bone tumour cells versus normal human cells.
  211. (1997). signal to FADDdependent apoptosis and activate NF-kappaB.
  212. (2008). Single-agent treatment with pegylated liposomal doxorubicin for metastatic breast cancer.
  213. (2008). Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases.
  214. (2000). Smac, a Mitochondrial Protein that Promotes Cytochrome c-Dependent Caspase Activation by Eliminating IAP Inhibition.
  215. (2008). Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAILresistant breast cancer cells.
  216. (2004). Smac/DIABLO selectively reduces the levels of cIAP1 and cIAP2 but not that of XIAP and livin in HeLa cells.
  217. (2009). Small molecule XIAP inhibitors enhance TRAIL-induced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma.
  218. (1999). Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis.
  219. (1997). Structure of Bcl-XL-Bak peptide complex: recognition between regulators of apoptosis.
  220. (2011). Synergistic anti-cancer effects via co-delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL/Apo2L) and doxorubicin using micellar nanoparticles.
  221. (2004). Synergistic induction of apoptosis in breast cancer cells by cotreatment with butyrate and TNFalpha, TRAIL or anti-FAS agonist antibody involves enhancement of death receptors' signalling and requires p21waf1.
  222. (2008). Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells.
  223. (2002). Targeting Death and Decoy Receptors of the Tumor-Necrosis Factor Superfamily.
  224. (2007). Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM).
  225. (2008). Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo.
  226. (2000). Temperature-sensitive Differential Affinity of TRAIL for Its Receptors.
  227. (1997). The cIAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases.
  228. (2000). The death domain kinase RIP is essential for TRAIL(Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase.
  229. (1889). The distribution of secondary growths in cancer of the breast.
  230. (1996). The epithelial to mesenchymal transition ad metastatic progression in carcinoma.
  231. (2006). The histone deacetylase inhibitor, suberolyanilide hydroxamic acid, overcomes resistance of human breast cancer cells to Apo2L/TRAIL.
  232. (2006). The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
  233. (2006). The inhibition and treatmetn of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors.
  234. (2008). The Nottingham prognostic index for invasive carcinoma of the breast.
  235. (1997). The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain.
  236. (1997). The Receptor for the Cytotoxic Ligand TRAIL.
  237. (2005). The role of apoptosis in cancer development and treatment response.
  238. (1998). The role of phosphatidylserine in recognition of apoptotic cells by phagocytes.
  239. (2002). The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a Reaper-like motif .
  240. (2003). The structure of a BclXL/Bim fragment complex: implications for Bim function.
  241. (2009). The TRAIL to targeted therapy of breast cancer.
  242. (2003). TNF-related apoptosis-inducing ligand mediates tumoricidal activity of human monocytes stimulated by Newcastle disease virus.
  243. (2010). TRAIL and doxorubicin combination induces proapoptotic and antiangiogenic effects in soft tissue sarcoma in vivo.
  244. (2007). TRAIL death receptor-4 expression positively correlates with the tumor grade in breast cancer patients with invasive ductal carcinoma.
  245. (2003). TRAIL induced survival and proliferation in cancer cells resistant towards TRAILinduced apoptosis mediated by NF-kappaB.
  246. (2004). TRAIL inhibits tumour growth but is non-toxic to human hepatocytes in chimeric mice.
  247. (2006). TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma.
  248. (2000). TRAIL receptor-2 signals apoptosis through FADD and caspase-8.
  249. (2008). TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5.
  250. (2010). TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5.
  251. (2007). TRAIL signals to apoptosis in chronic lymphocytic leukaemia cells primarily through TRAIL-R1 whereas cross-linked agonistic TRAIL-R2 antibodies facilitate signalling via TRAIL-R2.
  252. (2003). TRAIL-induced apoptosis and gene induction in HaCaT keratinocytes: differential contribution of TRAIL receptors 1 and 2.
  253. (2009). TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies.
  254. (2002). TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO.
  255. (2008). TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development.
  256. (2008). TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis.
  257. (1997). TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL.
  258. (1998). TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspase-dependent and caspase-independent pathways.
  259. (1997). TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL.
  260. (1998). TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling.
  261. (2001). Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: sensitivity of human thymocytes.
  262. (2005). Tumor necrosis factor-related apoptosis-inducing ligandmediated proliferation of tumor cells with receptor-proximal apoptosis defects.
  263. (1999). Tumor necrosis factor-related apoptosisinducing ligand receptors signal NF-kappaB and JNK activation and apoptosis through distinct pathways.
  264. (2002). Tumor-cell resistance to death receptor--induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax.
  265. (2001). Tumoricidal activity of a novel antihuman DR5 monoclonal antibody without hepatocyte cytotoxicity.
  266. (1999). Tumoricidal activity of tumor necrosis factorrelated apoptosis-inducing ligand in vivo.
  267. (2004). Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) decoy receptor TRAIL-R3 is up regulated by p53 in breast tumour cells through a mechanism involving an intronic p53-binding site.
  268. (2006). Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand Pathway and its Therapeutic Potentials Clin
  269. (1998). Two CD95 (APO-1/Fas) signaling pathways.
  270. (2006). Upregulation of TRAIL-R2 is not involved in the HDACi mediated sensitization to TRAIL-induced apoptosis.
  271. (1993). WAF1, a potent mediator of p53 tumor suppression.
  272. (2003). With A TRAIL-R1-Specific Ligand To Selectively Target TRAIL-Resistant Breast Tumour Cells For Apoptosis Shambhavi
  273. (1997). X-linked IAP is a direct inhibitor of cell-death proteases.
  274. (1996). X-ray and NMR structure of human Bcl-XL, an inhibitor of programmed cell death.
  275. (1995). Yama/CPP32β, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate Poly (ADPRibose)

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.