Abstract
TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, can induce apoptosis in cancer cells, sparing normal cells when bound to its associated death receptors (DR4/DR5). This unique mechanism makes TRAIL a potential anticancer therapeutic agent. However, clinical trials of recombinant TRAIL protein and TRAIL receptor agonist monoclonal antibodies have shown disappointing results due to its short half-life, poor pharmacokinetics and the resistance of the cancer cells. This review summarizes TRAIL-induced apoptotic and survival pathways as well as mechanisms leading to apoptotic resistance. Recent development of methods to overcome cancer cell resistance to TRAIL-induced apoptosis, such as protein modification, combination therapy and TRAIL-based gene therapy, appear promising. We also discuss the challenges and opportunities in the development of TRAIL-based therapies for the treatment of human cancers.
References
- 1. . Mechanisms and genes of cellular suicide. Science 267(5203), 1445–1449 (1995).
- 2. . Programmed cell death in animal development. Cell 88(3), 347–354 (1997).
- 3. . The hallmarks of cancer. Cell 100(1), 57–70 (2000).
- 4. . Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011).
- 5. . Apoptosis: a link between cancer genetics and chemotherapy. Cell 108(2), 153–164 (2002).
- 6. . Overview of cell death signaling pathways. Cancer. biol. Ther. 4(2), 139–163 (2005).
- 7. . Cross-talk in cell death signaling. J. Exp. Med. 192(8), F21–25 (2000).
- 8. Proapoptotic activation of death receptor 5 on tumor endothelial cells disrupts the vasculature and reduces tumor growth. Cancer cell 22(1), 80–90 (2012).
- 9. Induction of apoptosis by apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J. Biol. Chem. 271(22), 12687–12690 (1996).
- 10. . Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat. Rev. Drug. Discov. 7(12), 1001–1012 (2008).
- 11. Safety and antitumor activity of recombinant soluble apo2 ligand. J. Clin. Invest. 104(2), 155–162 (1999).
- 12. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J. Immunol. 166(8), 4891–4898 (2001).
- 13. Cooperation of the agonistic DR5 antibody apomab with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Clin. Cancer Res. 14(23), 7733–7740 (2008).
- 14. Combined treatment with lexatumumab and irradiation leads to strongly increased long term tumour control under normoxic and hypoxic conditions. Radiat. Oncol. 4, 49 (2009).
- 15. Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib. Mol. Cancer Ther. 8(2), 292–302 (2009).
- 16. . Getting TRAIL back on track for cancer therapy. Cell. Death. Differ. 21(9), 1350–1364 (2014).
- 17. . Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 14(3–4), 337–348 (2003).
- 18. . TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22(53), 8628–8633 (2003).
- 19. Triggering cell death: the crystal structure of apo2L/TRAIL in a complex with death receptor 5. Mol Cell 4(4), 563–571 (1999).
- 20. Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev. 37(4), 733–748 (2018).
- 21. The receptor for the cytotoxic ligand TRAIL. Science 276(5309), 111–113 (1997).
- 22. Characterization of two receptors for TRAIL. FEBS Lett. 416(3), 329–334 (1997).
- 23. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. The EMBO J. 16(17), 5386–5397 (1997).
- 24. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277(5327), 818–821 (1997).
- 25. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J. Exp. Med. 186(7), 1165–1170 (1997).
- 26. A novel receptor for apo2L/TRAIL contains a truncated death domain. Curr. Biol. CB 7(12), 1003–1006 (1997).
- 27. The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7(6), 813–820 (1997).
- 28. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J. Biol. Chem. 273(23), 14363–14367 (1998).
- 29. TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress. Oncotarget 8(6), 9974–9985 (2017).
- 30. . The TRAIL DISCussion: it is FADD and caspase-8! Cell Death Differ. 7(9), 759–760 (2000).
- 31. . FADD is required for DR4- and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts. J. Biol. Chem. 275(33), 25065–25068 (2000).
- 32. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137(4), 721–735 (2009).
- 33. TRAF2 sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer. Mol. Cell 48(6), 888–899 (2012).
- 34. BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ. 18(3), 538–548 (2011).
- 35. . XIAP, the guardian angel. Nat. Rev. Mol. Cell. Biol. 2(7), 550–556 (2001).
- 36. XIAP discriminates between Type I and Type II FAS-induced apoptosis. Nature 460(7258), 1035–1039 (2009).
- 37. . Apoptosis-inducing factor: vital and lethal. Trends Cell Biol. 16(5), 264–272 (2006).
- 38. A role of the mitochondrial apoptosis-inducing factor in granulysin-induced apoptosis. J. Immunol. 167(3), 1222–1229 (2001).
- 39. . Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J. Biol. Chem. 273(10), 5841–5845 (1998).
- 40. . Viral and cellular FLICE-inhibitory proteins: a comparison of their roles in regulating intrinsic immune responses. J. Virol. 88(12), 6539–6541 (2014).
- 41. Inhibition of death receptor signals by cellular FLIP. Nature 388(6638), 190–195 (1997).
- 42. c-FLIPR, a new regulator of death receptor-induced apoptosis. J. Biol. Chem. 280(15), 14507–14513 (2005).
- 43. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J. Biol. Chem. 276(23), 20633–20640 (2001).
- 44. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7(6), 831–836 (1997).
- 45. The death domain kinase RIP is essential for TRAIL (apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Mol. Cell. Biol. 20(18), 6638–6645 (2000).
- 46. . Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J. Biol. Chem. 280(16), 15709–15718 (2005).
- 47. MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. J. Biol. Chem. 276(19), 16484–16490 (2001).
- 48. Molecular determinants of kinase pathway activation by apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. J. Biol. Chem. 280(49), 40599–40608 (2005).
- 49. TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene 22(25), 3842–3852 (2003).
- 50. . Cell death induced by endoplasmic reticulum stress. FEBS J. 283(14), 2640–2652 (2016).
- 51. Molecular mechanism of ER stress-induced gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in macrophages. FEBS J. 282(12), 2361–2378 (2015).
- 52. . Activation of NF-kappaB by FADD, casper, and caspase-8. The J. Biol. Chem. 275(15), 10838–10844 (2000).
- 53. The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-kappaB by TRAIL. Cell Death Dis. 3, e414 (2012).
- 54. Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity. Oncogene 35(10), 1261–1270 (2016).
- 55. . Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer. Cell. Mol. Life Sci. 74(2), 245–255 (2017).
- 56. Death-receptor activation halts clathrin-dependent endocytosis. Proc. Natl. Acad. of Sci. USA 103(27), 10283–10288 (2006).
- 57. Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. J. Biol. Chem. 282(17), 12831–12841 (2007).
- 58. Death receptor 5 internalization is required for lysosomal permeabilization by TRAIL in malignant liver cell lines. Gastroenterology 136(7), 2365–2376 e2361–2367 (2009).
- 59. Importin beta1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells. J. Biol. Chem. 286(50), 43383–43393 (2011).
- 60. . Control of FLIP(L) expression and TRAIL resistance by the extracellular signal-regulated kinase1/2 pathway in breast epithelial cells. Cell Death Differ. 19(12), 1908–1916 (2012).
- 61. Caspase-8 mutations in head and neck cancer confer resistance to death receptor-mediated apoptosis and enhance migration, invasion, and tumor growth. Mol. Oncol. 8(7), 1220–1230 (2014).
- 62. . Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12(3), 228–237 (2005).
- 63. . Targeting TRAIL. Bioorg. Med. Chem. Lett. 29(18), 2527–2534 (2019).
- 64. Six1 overexpression in mammary cells induces genomic instability and is sufficient for malignant transformation. Cancer Res. 68(7), 2204–2213 (2008).
- 65. The TRAIL to cancer therapy: Hindrances and potential solutions. Crit. Rev. Oncol. Hematol. 143, 81–94 (2019).
- 66. . Pro-survival effects by NF-kappaB, Akt and ERK(1/2) and anti-apoptosis actions by Six1 disrupt apoptotic functions of TRAIL-Dr4/5 pathway in ovarian cancer. Biomed. Pharmacother. 84, 1078–1087 (2016).
- 67. Poly-ADP-ribosylation of HMGB1 regulates TNFSF10/TRAIL resistance through autophagy. Autophagy 11(2), 214–224 (2015).
- 68. TRAIL promotes membrane blebbing, detachment and migration of cells displaying a dysfunctional intrinsic pathway of apoptosis. Apoptosis 18(3), 324–336 (2013).
- 69. MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non-small-cell lung cancer through BIM down-regulation. Proc. Natl. Acad. Sci. USA 109(41), 16570–16575 (2012).
- 70. miR-221 augments TRAIL-mediated apoptosis in prostate cancer cells by inducing endogenous TRAIL expression and targeting the functional repressors SOCS3 and PIK3R1. Biomed res. Int. 2019, 6392748 (2019).
- 71. PD-L1 under regulation of miR-429 influences the sensitivity of gastric cancer cells to TRAIL by binding of EGFR. Front. Oncol. 10, 1067 (2020).
- 72. Downregulation of miR-125b promotes resistance of glioma cells to TRAIL through overexpression of Tafazzin which is a mitochondrial protein. Aging 11(9), 2670–2680 (2019).
- 73. . Trailing TRAIL resistance: novel targets for TRAIL sensitization in cancer cells. Front. Oncol. 5, 69 (2015).
- 74. . Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J. Clin. Oncol. 26(21), 3621–3630 (2008).
- 75. . Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer 17(6), 352–366 (2017).
- 76. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. Clin. cancer Res. 12(8), 2640–2646 (2006).
- 77. Differential hepatocyte toxicity of recombinant apo2L/TRAIL versions. Nat. Med. 7(4), 383–385 (2001).
- 78. Preclinical studies to predict the disposition of apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J. Pharmacol. and Exp. Ther. 299(1), 31–38 (2001).
- 79. Phase I dose-escalation study of recombinant human apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J. Clin. Oncol. 28(17), 2839–2846 (2010).
- 80. Targeting the apoptotic pathway in chondrosarcoma using recombinant human apo2L/TRAIL (dulanermin), a dual proapoptotic receptor (DR4/DR5) agonist. Mol. cancer Ther. 11(11), 2541–2546 (2012).
- 81. Tissue distribution, stability, and pharmacokinetics of apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in human colon carcinoma COLO205 tumor-bearing nude mice. Drug Metab. Dispo. 32(11), 1230–1238 (2004).
- 82. Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Mol. Cell. Biol. 26(19), 7046–7055 (2006).
- 83. . TRAIL therapy and prospective developments for cancer treatment. J. Control. Release 326, 335–349 (2020).
- 84. Relationship between the agonist activity of synthetic ligands of TRAIL-R2 and their cell surface binding modes. Oncotarget 9(21), 15566–15578 (2018).
- 85. . Antibodies and derivatives targeting DR4 and DR5 for cancer therapy. Antibodies 6(4), 16 (2017).
- 86. Improvement of pharmacokinetic profile of TRAIL via trimer-tag enhances its antitumor activity in vivo. Sci. Rep. 7(1), 8953 (2017).
- 87. Customizing a tri-domain TRAIL variant to achieve active tumor homing and endogenous albumin-controlled release of the molecular machine in vivo. Biomacromolecules 21(10), 4017–4029 (2020).
- 88. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat. Med. 7(8), 954–960 (2001).
- 89. Effect of anti-DR5 and chemotherapy on basal-like breast cancer. Breast cancer Res. 133(2), 417–426 (2012).
- 90. Anti-tumor activity of TRA-8 anti-death receptor 5 (DR5) monoclonal antibody in combination with chemotherapy and radiation therapy in a cervical cancer model. Gynecol. Oncol. 101(1), 46–54 (2006).
- 91. Treatment with gemcitabine and TRA-8 anti-death receptor-5 mAb reduces pancreatic adenocarcinoma cell viability in vitro and growth in vivo. J. Gastrointest. Surg. 10(9), 1291–1300 (2006).
- 92. . Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model. Cancer Lett. 251(1), 146–157 (2007).
- 93. A novel humanized anti-human death receptor 5 antibody CS-1008 induces apoptosis in tumor cells without toxicity in hepatocytes. Ann. Oncol. 19(6), 1060–1067 (2008).
- 94. Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types. Cancer Biol. Ther. 9(8), 618–631 (2010).
- 95. . Conatumumab, a fully human mAb against death receptor 5 for the treatment of cancer. Curr. Opin. Investig. Drugs 11(6), 688–698 (2010).
- 96. Treatment of human colon cancer xenografts with TRA-8 anti-death receptor 5 antibody alone or in combination with CPT-11. Clin. Cancer Res. 14(7), 2180–2189 (2008).
- 97. The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells. Cell Death Dis. 9(5), 445 (2018).
- 98. Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Clin. Lung Cancer 15(3), 188–196 e182 (2014).
- 99. Induction of apoptosis by monoclonal antibody anti-apo-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J. Immunol. 149(10), 3166–3173 (1992).
- 100. Structural and functional analysis of the interaction between the agonistic monoclonal antibody apomab and the proapoptotic receptor DR5. Cell Death Differ. 15(4), 751–761 (2008).
- 101. . Targeting apo2L/TRAIL receptors by soluble apo2L/TRAIL. Cancer Lett. 332(2), 156–162 (2013).
- 102. Multivalent nanobodies targeting death receptor 5 elicit superior tumor cell killing through efficient caspase induction. mAbs 6(6), 1560–1570 (2014).
- 103. Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody(R) targeting the DR5 receptor. Cancer Chemother. Pharmacol. 75(5), 887–895 (2015).
- 104. Expression of TRAIL and TRAIL receptors in colon carcinoma: TRAIL-R1 is an independent prognostic parameter. Clin. Cancer Res. 8(12), 3734–3740 (2002).
- 105. Expression of TRAIL and TRAIL death receptors in stage III non-small cell lung cancer tumors. Clin. Cancer Res. 9(9), 3397–3405 (2003).
- 106. Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin. Cancer Res. 16(22), 5529–5538 (2010).
- 107. Cytoplasmic TRAIL-R1 is a positive prognostic marker in PDAC. BMC Cancer 18(1), 777 (2018).
- 108. . Expression of tumor necrosis factor-related apoptosis-inducing ligand death receptors DR4 and DR5 in human nonmelanoma skin cancer. Am. J. Dermatopathol. 36(9), 710–717 (2014).
- 109. Death receptor 5 (DR5) and a 5-gene apoptotic biomarker panel with significant differential diagnostic potential in colorectal cancer. Sci. Rep. 6, 36532 (2016).
- 110. TRAIL receptors are differentially regulated and clinically significant in gallbladder cancer. Pathology 52(3), 348–358 (2020).
- 111. Evaluating the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in breast cancer. Clin. Cancer Res. 11(14), 5188–5194 (2005).
- 112. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme. J. Neurooncol. 78(2), 161–171 (2006).
- 113. Prognostic value of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors in renal cell cancer. Clin. Cancer Res. 15(2), 650–659 (2009).
- 114. Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery. PLoS ONE 8(2), e56760 (2013).
- 115. Nuclear death receptor TRAIL-R2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells. Gastroenterology 146(1), 278–290 (2014).
- 116. Prognostic significance of TRAIL-R1 and TRAIL-R3 expression in metastatic colorectal carcinomas. Eur. J. Cancer 44(15), 2312–2318 (2008).
- 117. High TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which can be overcome by targeting TRAIL-R2. Leuk. Res. 35(6), 741–749 (2011).
- 118. Membrane expression of trail receptors DcR1 and DcR2 in the normal endometrium, endometrial atypical hyperplasia and endometrioid endometrial cancer. J. Obstet. Gynaecol. 34(4), 346–349 (2014).
- 119. Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer. BMC Cancer 17(1), 280 (2017).
- 120. Epigenetic inactivation of TRAIL decoy receptors at 8p12–21.3 commonly deleted region confers sensitivity to Apo2L/trail-Cisplatin combination therapy in cervical cancer. Genes Chromosomes Cancer 55(2), 177–189 (2016).
- 121. Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer. J. Mol. Med. 87(10), 995–1007 (2009).
- 122. Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer. Oncotarget 8(38), 63140–63154 (2017).
- 123. Comprehensive expression analysis of TNF-related apoptosis-inducing ligand and its receptors in colorectal cancer: Correlation with MAPK alterations and clinicopathological associations. Pathol. Res. Pract. 214(6), 826–834 (2018).
- 124. Nanocarriers for TRAIL delivery: driving TRAIL back on track for cancer therapy. Nanoscale 9(37), 13879–13904 (2017).
- 125. Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Cancer Res. 61(8), 3330–3338 (2001).
- 126. Liposomes decorated with apo2L/TRAIL overcome chemoresistance of human hematologic tumor cells. Mol. Pharm. 10(3), 893–904 (2013).
- 127. Overcoming gene-delivery hurdles: physiological considerations for nonviral vectors. Trends Biotechnol. 34(2), 91–105 (2016).
- 128. Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/apo-2 ligand gene induces tumor cell apoptosis. J. Immunol. 165(5), 2886–2894 (2000).
- 129. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 15(8), 541–555 (2014).
- 130. Biosilicified oncolytic adenovirus for cancer viral gene therapy. Biomater. Sci. 8, 5317–5328 (2020).
- 131. . Design and development of polymers for gene delivery. Nat. Rev. Drug Dis. 4(7), 581–593 (2005).
- 132. . Nonviral vectors for gene delivery. Chem. Rev. 109(2), 259–302 (2009).
- 133. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl. Acad. Sci. USA 92(16), 7297–7301 (1995).
- 134. Co-delivery of gambogic acid and TRAIL plasmid by hyaluronic acid grafted PEI-PLGA nanoparticles for the treatment of triple negative breast cancer. Drug Deliv. 24(1), 1791–1800 (2017).
- 135. The use of myristic acid as a ligand of polyethylenimine/DNA nanoparticles for targeted gene therapy of glioblastoma. Nanotechnology 22(43), 435101 (2011).
- 136. . Polymeric nanoparticle-based delivery of TRAIL DNA for cancer-specific killing. Bioeng. Transl. Med. 1(2), 149–159 (2016).
- 137. . Metal-based phosphorus dendrimers as novel nanotherapeutic strategies to tackle cancers: A concise overview. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11(6), e1577 (2019).
- 138. TRAIL in oncology: from recombinant TRAIL to nano- and self-targeted TRAIL-based therapies. Pharmacol. Res. 155, 104716 (2020).
- 139. Nanoparticle-mediated target delivery of TRAIL as gene therapy for glioblastoma. Adv. Healthc. Mater. 4(17), 2719–2726 (2015).
- 140. . Sandwich-type Au-PEI/DNA/PEI-Dexa nanocomplex for nucleus-targeted gene delivery in vitro and in vivo. ACS Appl. Mater. Inter. 6(16), 14196–14206 (2014).
- 141. TRAIL-NP hybrids for cancer therapy: a review. Nanoscale 9(18), 5755–5768 (2017).
- 142. . Peptide-guided gene delivery. The AAPS J. 9(1), E18–29 (2007).
- 143. Generation and characterization of novel anti-DR4 and anti-DR5 antibodies developed by genetic immunization. Cell Death Dis. 10(2), 101 (2019).
- 144. Multifunctional “core-shell” nanoparticles-based gene delivery for treatment of aggressive melanoma. Biomaterials 111, 124–137 (2016).
- 145. Multifunctional nucleus-targeting nanoparticles with ultra-high gene transfection efficiency for in vivo gene therapy. Theranostics 7(6), 1633–1649 (2017).
- 146. TRAIL acts synergistically with iron oxide nanocluster-mediated magneto- and photothermia. Theranostics 9(20), 5924–5936 (2019).
- 147. . Regulation of the human TRAIL gene. Cancer Biol. Ther. 13(12), 1143–1151 (2012).
- 148. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat. Med. 7(6), 680–686 (2001).
- 149. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat. Med. 11(1), 77–84 (2005).
- 150. . Epigenetic regulation of TRAIL signaling: implication for cancer therapy. Cancers 11(6)2019).
- 151. . Tumor necrosis factor-related apoptosis-inducing ligand is required for tumor necrosis factor alpha-mediated sensitization of human breast cancer cells to chemotherapy. Cancer Res. 66(20), 10092–10099 (2006).
- 152. . Evidence that tumor necrosis factor-related apoptosis-inducing ligand induction by 5-Aza-2′-deoxycytidine sensitizes human breast cancer cells to adriamycin. Cancer Res. 67(3), 1203–1211 (2007).
- 153. Sp1-mediated TRAIL induction in chemosensitization. Cancer Res. 68(16), 6718–6726 (2008).
- 154. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci. Transl. Med. 5(171), 171ra117 (2013).
- 155. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget 7(45), 74380–74392 (2016).
- 156. . Small-molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner. Cancer Res. 75(7), 1423–1432 (2015).
- 157. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci. Signal. 9(415), ra17 (2016).
- 158. ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells. Oncotarget 8(13), 21626–21638 (2017).
- 159. First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors. Clin. Cancer Res. 23(15), 4163–4169 (2017).
- 160. Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res. 60(4), 847–853 (2000).
- 161. Enhancement of TRAIL/apo2L-mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells. Int. J. Cancer 104(4), 409–417 (2003).
- 162. Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Mol. Cell. Biol. 20(1), 205–212 (2000).
- 163. . Sensitization of recombinant human tumor necrosis factor-related apoptosis-inducing ligand-resistant malignant melanomas by quercetin. Melanoma Res. 28(4), 277–285 (2018).
- 164. Proteasome inhibitor MG132 potentiates TRAIL-induced apoptosis in gallbladder carcinoma GBC-SD cells via DR5-dependent pathway. Oncol. Rep. 36(2), 845–852 (2016).
- 165. . Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res. 64(18), 6666–6672 (2004).
- 166. Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors: evidence for the role of c-Jun N-terminal kinase activation. Cell cycle 11(17), 3312–3323 (2012).
- 167. Identification of mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme. Cancer Biol. Ther. 17(5), 546–557 (2016).
- 168. Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1. Mol. Cancer Ther. 6(4), 1387–1399 (2007).
- 169. Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL. Br. J. Cancer 109(10), 2685–2695 (2013).
- 170. Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptor 5 (DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells. Cancer Lett. 287(1), 98–108 (2010).
- 171. . The alkyllysophospholipid edelfosine enhances TRAIL-mediated apoptosis in gastric cancer cells through death receptor 5 and the mitochondrial pathway. Tumour Biol. 37(5), 6205–6216 (2016).
- 172. Inhibition of Notch1 signaling overcomes resistance to the death ligand Trail by specificity protein 1-dependent upregulation of death receptor 5. Cell Death Dis. 6, e1921 (2015).
- 173. Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors. Free Radic. Biol. Med. 53(10), 1977–1987 (2012).
- 174. ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer. Cancer Biol. Ther. 16(8), 1194–1204 (2015).
- 175. Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation. Cell Death Dis. 7(8), e2334 (2016).
- 176. Chikusetsusaponin IVa butyl ester (CS-IVa-Be), a novel IL6R antagonist, inhibits IL6/STAT3 signaling pathway and induces cancer cell apoptosis. Mol. Cancer Ther. 15(6), 1190–1200 (2016).
- 177. Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through up-regulation of death receptors and down-regulation of survival proteins: role of ROS-dependent CCAAT/enhancer-binding protein-homologous protein pathway. Antioxid. Redox Signal. 16(5), 413–427 (2012).
- 178. . Medicarpin, a legume phytoalexin sensitizes myeloid leukemia cells to TRAIL-induced apoptosis through the induction of DR5 and activation of the ROS-JNK-CHOP pathway. Cell Death Dis. 5, e1465 (2014).
- 179. Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL-induced cytotoxicity by quercetin in non-small cell lung cancer cells. Carcinogenesis 28(10), 2114–2121 (2007).
- 180. Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells. Blood 108(2), 630–637 (2006).
- 181. Luteolin enhances TRAIL sensitivity in non-small cell lung cancer cells through increasing DR5 expression and Drp1-mediated mitochondrial fission. Arch. Biochem. Biophys. 692, 108539 (2020).
- 182. Wogonin and related natural flavones overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein resistance of tumors by down-regulation of c-FLIP protein and up-regulation of TRAIL receptor 2 expression. J. Biol. Chem. 287(1), 641–649 (2012).
- 183. . TRAIL-based gene delivery and therapeutic strategies. Acta pharmacol. Sin. 40(11), 1373–1385 (2019).