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Deng, L. TRAIL-based Therapy for GBM. Encyclopedia. Available online: https://encyclopedia.pub/entry/9052 (accessed on 07 July 2024).
Deng L. TRAIL-based Therapy for GBM. Encyclopedia. Available at: https://encyclopedia.pub/entry/9052. Accessed July 07, 2024.
Deng, Longfei. "TRAIL-based Therapy for GBM" Encyclopedia, https://encyclopedia.pub/entry/9052 (accessed July 07, 2024).
Deng, L. (2021, April 27). TRAIL-based Therapy for GBM. In Encyclopedia. https://encyclopedia.pub/entry/9052
Deng, Longfei. "TRAIL-based Therapy for GBM." Encyclopedia. Web. 27 April, 2021.
TRAIL-based Therapy for GBM
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This entry is adapted from the peer-reviewed paper 10.3390/biom11040572

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. This entry is defined by some potential stratergies of applying TRAIL-based therapy via overriding resistance for GBM trearment.

TRAIL death receptor resistance glioblastoma

1. Introduction

To maximize the potential of TRAIL in treating GBM, most research has focused on developing methods to sensitize GBM to TRAIL treatment through two major directions: increasing TRAIL bioavailability via constructing efficient TRAIL delivery system and enhancing TRAIL tumoricidal activity through combining sensitizing drugs. 

2. Sensitizing GBM to TRAIL-Induced Apoptosis

2.1. Nanoparticle Delivery

The clinical application of TRAIL is largely hindered by its short serum half-life and lack of efficient delivery approaches. In recent years, developing nanoparticles as carriers in gene therapy has been considered as an effective approach to increase TRAIL delivery to tumors as transfected cells will specifically secrete TRAIL into the tumor microenvironment. However, another huge obstacle for gene delivery to GBM in the brain is to cross the blood–brain barrier, and most delivery vehicles fail to generate high gene transfection efficiency in vivo[1]. By developing a targeted iron oxide nanoparticle coated with chitosan-polyethylene glycol-polyethyleneimine copolymer and chlorotoxin, one study has found that this delivery system successfully delivers TRAIL into human GBM cells and induces secretion of TRAIL in vitro and in vivo, resulting in near-zero tumor growth and induces apoptosis in tumor tissue[2]. This study suggests that nanoparticle-mediated TRAIL delivery can serve as a potential targeted therapeutic for more efficient TRAIL delivery to GBM. A similar concept has been applied to human adipose-derived stem cells (hADSCs), in which polymeric nanoparticles, as a drug-delivery vehicle, mediate the overexpression of TRAIL for targeting and eradicating GBM cells in vivo and prolong animal survival[3]. A recent study also reveals that TRAIL sensitivity in GBM cells can be enhanced by conjugation of TRAIL with silver nanoparticles, further supporting nanoparticle delivery to be a promising therapeutic approach to bypass consumption of TRAIL in circulation and effectively increase the TRAIL dose in tumor lesions for sensitizing TRAIL resistance[4].

2.2. Combination with Chemotherapeutic Drugs

Most chemotherapeutic drugs kill cancer cells predominantly by triggering the apoptotic program. Increasing evidence has shown that several chemotherapeutic drugs treated in combination with TRAIL can result in the reversal of GBM resistance to TRAIL-mediated apoptosis. For example, combined TRAIL plus paclitaxel have cooperative anti-GBM efficacy in vivo, particularly with no discernable toxicity to normal tissue[5]. Analogically, co-delivery of the TRAIL gene also enhances the antitumor activity of paclitaxel against GBM cells in vitro and in vivo[6]. Except paclitaxel, a synergistic anti-GBM effect has been validated between TRAIL and cisplatin, as evidenced by cisplatin-enhanced sensitivity of GBM cells to adenovirus-delivered TRAIL[7], and cisplatin-restored activation of the TRAIL apoptotic pathway in GBM-derived stem cells[8]. Moreover, doxorubicin and mitoxantrone were also identified as TRAIL-sensitizing agents for GBM[9][10]. Interestingly, L-asparaginase, a metabolic enzyme used in the treatment of acute lymphatic leukaemia by hydrolyzing asparagine, potently overcomes GBM cell resistance to TRAIL-induced extrinsic apoptosis[11]. Together, these preclinical observations suggest the therapeutic potential of combining TRAIL plus chemotherapeutic drugs in GBM treatment and encourage further preclinical and future clinical tests.

2.3. Combination with Non-Chemotherapeutic Drugs

Compared with chemotherapeutic drugs, efficacious synergistic effects of non-chemotherapeutic agents and TRAIL may be uncommon. However, evidence has indicated that lovastatin, a lipid-reducing drug, enhances TRAIL-induced GBM cell apoptosis synergistically[12]. Another example is salinomycin, an antibiotic used in the poultry industries to eliminate coccidiosis, which potentiates the cytotoxic effects of TRAIL on GBM cell lines[13]. Moreover, quinacrine is a small molecule antimalarial agent that was recently recognized with anticancer potentials[14], and it has been demonstrated that quinacrine is able to mediate the sensitization of GBM cells to TRAIL treatment[15], suggesting a combination treatment for GBM therapy. Other non-chemotherapeutic drugs exhibiting TRAIL-sensitizing activity include nelfinavir[16], troglitazone[17], digitoxin[18], melatonin[19], and Lanatoside C[20]. One of the limitations of these studies is a shortage of clarity regarding the molecular mechanisms accounting for the synergistic effects of these non-chemotherapeutic drugs and TRAIL, which require further investigations.

2.4. Combination with Other Inhibitors

Aside from inhibitors of the Akt-mTOR-S6K1 pathway, KPNB1, and PIM kinases, a large growing body of studies have also shown that a variety of inhibitors that do not belong to therapeutic drugs but sensitize GBM to TRAIL-induced apoptosis. For instance, histone deacetylase inhibitors (HDACIs), such as MS275, suberoylanilide hydroxamic acid and valproic acid, sensitize GBM cells to TRAIL-induced apoptosis in vitro and in vivo through c-myc-downregulated c-FLIP[21], suggesting the use of HDACIs in order to prime GBM for TRAIL-induced apoptosis by targeting c-FLIP. Since the anti-apoptotic Bcl-2 family members play a critical role in determining GBM sensitivity to TRAIL-induced apoptosis, inhibitors of this family members (BH3-mimetics), such as ABT-737[22] and ABT-199[23], were found to cooperate with TRAIL to induce apoptosis in several GBM cell lines in a highly synergistic manner. These results outline the antagonism of surviving machinery as a highly potent intervention to sensitize GBM cells to TRAIL combination treatment. Protein synthesis inhibitors, such as cycloheximide, can reverse the resistance of some cancer cells to TRAIL[24]. Two studies have revealed that the proteasome inhibitor bortezomib primes GBM, including GBM stem cells, for TRAIL sensitization, which is dependent on increased tBid stability, mitochondrial apoptosis, and modulation of the NF-κB signaling pathway[25][26]. Consistent with these reports, pretreating GBM with bortezomib potentiates natural killer cell cytotoxicity to induce TRAIL-mediated apoptosis and prolongs animal survival[27]. Taken together, these findings provide compelling evidence that the combination of bortezomib and TRAIL presents a promising strategy to promote TRAIL sensitization and trigger apoptosis in GBM.

3. Conclusions

Owing to excusive the tumoricidal property revealed by a large amount of pre-clinical and clinical studies, it is believed that targeting the TRAIL/TRAIL-R1/R2 axis holds great promise to be harnessed in combinatorial therapies for treating cancers, including GBM, a deadly cancer without efficacious therapeutic options. However, employing either recombinant human TRAIL or agonist antibodies against TRAIL-R1/2 to reactive the extrinsic apoptosis pathway in cancer cells for cancer therapy has yielded undesirable outcomes in previous clinical trials, casting a shadow over the future clinical applications of this strategy. Currently, seeking methods to overcome TRAIL resistance for enhancing TRAIL efficacy is a research focus. As with many cancers, the majority of GBM tumors are generally resistant to TRAIL-induced apoptosis largely due to several aberrations in genetics that result in low or loss of expression of apoptotic genes and simultaneous overexpression of anti-apoptotic genes, which comprise the TRAIL-induced apoptotic signaling pathway. Attempts to understand the mechanisms of TRAIL-induced apoptotic signaling in GBM have unraveled novel regulators in promoting or inhibiting TRAIL resistance, mainly through modulating the levels or activation of TRAIL-R1/R2, c-FLIP, caspase-8, and DISC. These studies provide novel therapeutic targets that can potentially interfere the resistance mechanisms to overcome GBM resistance to TRAIL-based therapies. Another strategy to improve the therapeutic efficacy of TRAIL and sensitize TRAIL resistance in GBM is through developing more effective approaches of delivering a sufficient amount of TRAIL to tumor lesions in the brain. Recent studies have shown the advantages of nanoparticles in increasing the delivery efficiency of TRAIL to sensitize GBM to TRAIL treatment. In addition, sensitizing GBM to TRAIL-induced apoptosis has proven effective by multiple preclinical studies through the combinatorial treatment of TRAIL with other agents, such as some commonly used chemotherapeutic and non-chemotherapeutic drugs and synthetic inhibitors. According to these progresses in overcoming TRAIL resistance in GBM, we expect more clinical trials will participate to test the therapeutic potency and safety of TRAIL-based combination modalities in GBM treatment. Finally, however, despite the abovementioned advances, how GBM tumors acquire TRAIL resistance is still not fully understood, and the mechanisms underlying synergistic effect of TRAIL and chemotherapeutic or non-chemotherapeutic drugs remain largely unexploited. Addressing these challenges is needed to overcome TRAIL resistance for maximizing the therapeutic potential of TRAIL in treating GBM.

References

  1. Ho Lun Wong; Xiao Yu Wu; Reina Bendayan; Nanotechnological advances for the delivery of CNS therapeutics. Advanced Drug Delivery Reviews 2012, 64, 686-700, 10.1016/j.addr.2011.10.007.
  2. Kui Wang; Forrest M. Kievit; Mike Jeon; John R. Silber; Richard G. Ellenbogen; Miqin Zhang; Nanoparticle-Mediated Target Delivery of TRAIL as Gene Therapy for Glioblastoma. Advanced Healthcare Materials 2015, 4, 2719-2726, 10.1002/adhm.201500563.
  3. Xinyi Jiang; Sergio Fitch; Christine Wang; Christy Wilson; Jianfeng Li; Gerald A. Grant; Fan Yang; Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery. Proceedings of the National Academy of Sciences 2016, 113, 13857-13862, 10.1073/pnas.1615396113.
  4. Ilknur Sur-Erdem; Kerem Muslu; Nareg Pınarbası; Mine Altunbek; Fidan Seker-Polat; Ahmet Cingöz; Serdar Onur Aydın; Mehmet Kahraman; Mustafa Culha; Ihsan Solaroglu; et al.Tugba Bagcı-Önder TRAIL-conjugated silver nanoparticles sensitize glioblastoma cells to TRAIL by regulating CHK1 in the DNA repair pathway. Neurological Research 2020, 42, 1061-1069, 10.1080/01616412.2020.1796378.
  5. Jay F. Dorsey; Akiva Mintz; Xiaobing Tian; Melissa L. Dowling; John P. Plastaras; David T. Dicker; Gary D. Kao; Wafik S. El-Deiry; Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells. Molecular Cancer Therapeutics 2009, 8, 3285-3295, 10.1158/1535-7163.mct-09-0415.
  6. Changyou Zhan; Xiaoli Wei; Jun Qian; Linglin Feng; Jianhua Zhu; Weiyue Lu; Co-delivery of TRAIL gene enhances the anti-glioblastoma effect of paclitaxel in vitro and in vivo. Journal of Controlled Release 2012, 160, 630-636, 10.1016/j.jconrel.2012.02.022.
  7. Jian Chen; Xiaobai Sun; Weihua Yang; Guosheng Jiang; Xingang Li; Cisplatin-enhanced sensitivity of glioblastoma multiforme U251 cells to adenovirus-delivered TRAIL in vitro. Tumor Biology 2010, 31, 613-622, 10.1007/s13277-010-0077-x.
  8. Lijuan Ding; Changji Yuan; Feng Wei; Guangyi Wang; Jing Zhang; Anita C. Bellail; Zhaobin Zhang; Jeffrey J. Olson; Chunhai Hao; Cisplatin Restores TRAIL Apoptotic Pathway in Glioblastoma-Derived Stem Cells through Up-regulation of DR5 and Down-regulation of c-FLIP. Cancer Investigation 2011, 29, 511-520, 10.3109/07357907.2011.605412.
  9. Liangran Guo; Li Fan; Zhiqing Pang; Jinfen Ren; Yulong Ren; Jingwei Li; Jie Chen; Ziyi Wen; Xinguo Jiang; TRAIL and doxorubicin combination enhances anti-glioblastoma effect based on passive tumor targeting of liposomes. Journal of Controlled Release 2011, 154, 93-102, 10.1016/j.jconrel.2011.05.008.
  10. Filiz Senbabaoglu; Ahmet Cingoz; Ezgi Kaya; Selena Kazancioglu; Nathan A. Lack; Ceyda Acilan; Tugba Bagci-Onder; Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme. Cancer Biology & Therapy 2016, 17, 546-557, 10.1080/15384047.2016.1167292.
  11. Georg Karpel-Massler; Doruntina Ramani; Chang Shu; Marc-Eric Halatsch; Mike-Andrew Westhoff; Jeffrey N. Bruce; Peter Canoll; Markus D. Siegelin; Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo. Oncotarget 2016, 7, 33512-33528, 10.18632/oncotarget.9257.
  12. David Y. L. Chan; George G. Chen; Wai S. Poon; Pi C. Liu; Lovastatin sensitized human glioblastoma cells to TRAIL-induced apoptosis. Journal of Neuro-Oncology 2007, 86, 273-283, 10.1007/s11060-007-9475-3.
  13. Alessia Calzolari; Ernestina Saulle; Maria Laura De Angelis; Luca Pasquini; Alessandra Boe; Federica Pelacchi; Lucia Ricci-Vitiani; Marta Baiocchi; Ugo Testa; Salinomycin Potentiates the Cytotoxic Effects of TRAIL on Glioblastoma Cell Lines. PLOS ONE 2014, 9, e94438, 10.1371/journal.pone.0094438.
  14. Derek B. Oien; Christopher L. Pathoulas; Upasana Ray; Prabhu Thirusangu; Eleftheria Kalogera; Viji Shridhar; Repurposing quinacrine for treatment-refractory cancer. Seminars in Cancer Biology 2021, 68, 21-30, 10.1016/j.semcancer.2019.09.021.
  15. Pelin Erkoc; Ahmet Cingoz; Tugba Bagci Onder; Seda Kizilel; Quinacrine Mediated Sensitization of Glioblastoma (GBM) Cells to TRAIL through MMP-Sensitive PEG Hydrogel Carriers. Macromolecular Bioscience 2016, 17, 1600267, 10.1002/mabi.201600267.
  16. Xiaobing Tian; Jiangbin Ye; Michelle Alonso-Basanta; Stephen M. Hahn; Constantinos Koumenis; Jay F. Dorsey; Modulation of CCAAT/Enhancer Binding Protein Homologous Protein (CHOP)-dependent DR5 Expression by Nelfinavir Sensitizes Glioblastoma Multiforme Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL). Journal of Biological Chemistry 2011, 286, 29408-29416, 10.1074/jbc.m110.197665.
  17. Kerstin Schultze; Barbara Böck; Anika Eckert; Lena Oevermann; Dirk Ramacher; Otmar Wiestler; Wilfried Roth; Troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via down-regulation of FLIP and Survivin. Apoptosis 2006, 11, 1503-1512, 10.1007/s10495-006-8896-3.
  18. Dae-Hee Lee; Chang Sup Lee; Dong-Wook Kim; Jeh Eun Ae; Tae-Hwa Lee; Digitoxin sensitizes glioma cells to TRAIL-mediated apoptosis by upregulation of death receptor 5 and downregulation of survivin. Anti-Cancer Drugs 2014, 25, 44-52, 10.1097/cad.0000000000000015.
  19. Vanesa Martín; Guillermo García-Santos; Jezabel Rodriguez-Blanco; Sara Casado-Zapico; Ana Sanchez-Sanchez; Isaac Antolín; Maria Medina; Carmen Rodriguez; Melatonin sensitizes human malignant glioma cells against TRAIL-induced cell death. Cancer Letters 2010, 287, 216-223, 10.1016/j.canlet.2009.06.016.
  20. Christian E. Badr; Thomas Wurdinger; Jonas Nilsson; Johanna M. Niers; Michael Whalen; Alexei Degterev; Bakhos A. Tannous; Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor–related apoptosis-inducing ligand and induces an alternative cell death pathway. Neuro-Oncology 2011, 13, 1213-1224, 10.1093/neuonc/nor067.
  21. A Bangert; S Cristofanon; I Eckhardt; B A Abhari; S Kolodziej; Stephan M Hacker; Sri Hari Krishna Vellanki; Jorn Lausen; K-M Debatin; Simone Fulda; et al. Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene 2012, 31, 4677-4688, 10.1038/onc.2011.614.
  22. S Cristofanon; Simone Fulda; ABT-737 promotes tBid mitochondrial accumulation to enhance TRAIL-induced apoptosis in glioblastoma cells. Cell Death & Disease 2012, 3, e432-e432, 10.1038/cddis.2012.163.
  23. Frank A. Lincoln; Dirke Imig; Chiara Boccellato; Viktorija Juric; Janis Noonan; Roland E. Kontermann; Frank Allgöwer; Brona M. Murphy; Markus Rehm; Sensitization of glioblastoma cells to TRAIL-induced apoptosis by IAP- and Bcl-2 antagonism. Cell Death & Disease 2018, 9, 1-14, 10.1038/s41419-018-1160-2.
  24. Harald Wajant; Elvira Haas; Ralph Schwenzer; Frank Mühlenbeck; Sebastian Kreuz; Gisela Schubert; Matthias Grell; Craig Smith; Peter Scheurich; Inhibition of Death Receptor-mediated Gene Induction by a Cycloheximide-sensitive Factor Occurs at the Level of or Upstream of Fas-associated Death Domain Protein (FADD). Journal of Biological Chemistry 2000, 275, 24357-24366, 10.1074/jbc.m000811200.
  25. Thomas Unterkircher; Silvia Cristofanon; Sri Hari Krishna Vellanki; Lisa Nonnenmacher; Georg Karpel-Massler; Christian Rainer Wirtz; Klaus-Michael Debatin; Simone Fulda; Bortezomib Primes Glioblastoma, Including Glioblastoma Stem Cells, for TRAIL by Increasing tBid Stability and Mitochondrial Apoptosis. Clinical Cancer Research 2011, 17, 4019-4030, 10.1158/1078-0432.ccr-11-0075.
  26. Esther P. Jane; Daniel R. Premkumar; Ian F. Pollack; Bortezomib Sensitizes Malignant Human Glioma Cells to TRAIL, Mediated by Inhibition of the NF-κB Signaling Pathway. Molecular Cancer Therapeutics 2011, 10, 198-208, 10.1158/1535-7163.mct-10-0725.
  27. Andrea Gras Navarro; Heidi Espedal; Justin Vareecal Joseph; Laura Trachsel-Moncho; Marzieh Bahador; Bjørn Tore Gjertsen; Einar Klæboe Kristoffersen; Anne Simonsen; Hrvoje Miletic; Per Øyvind Enger; et al.Mohummad Aminur RahmanMartha Chekenya Pretreatment of Glioblastoma with Bortezomib Potentiates Natural Killer Cell Cytotoxicity through TRAIL/DR5 Mediated Apoptosis and Prolongs Animal Survival. Cancers 2019, 11, 996, 10.3390/cancers11070996.
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Longfei Deng
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