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Thang M, Mellows C, Kass LE, Daglish S, Fennell EM, Mann BE, Mercer-Smith AR, Valdivia A, Graves LM, Hingtgen SD. Combining the constitutive TRAIL-secreting induced neural stem cell therapy with the novel anti-cancer drug TR-107 in glioblastoma. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200834. [PMID: 39045029 PMCID: PMC11263637 DOI: 10.1016/j.omton.2024.200834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 01/27/2024] [Accepted: 06/13/2024] [Indexed: 07/25/2024]
Abstract
Tumor-homing neural stem cell (NSC) therapy is emerging as a promising treatment for aggressive cancers of the brain. Despite their success, developing tumor-homing NSC therapy therapies that maintain durable tumor suppression remains a challenge. Herein, we report a synergistic combination regimen where the novel small molecule TR-107 augments NSC-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy (hiNeuroS-TRAIL) in models of the incurable brain cancer glioblastoma (GBM) in vitro. We report that the combination of hiNeuroS-TRAIL and TR-107 synergistically upregulated caspase markers and restored sensitivity to the intrinsic apoptotic pathway by significantly downregulating inhibitory pathways associated with chemoresistance and radioresistance in the TRAIL-resistant LN229 cell line. This combination also showed robust tumor suppression and enhanced survival of mice bearing human xenografts of both solid and invasive GBMs. These findings elucidate a novel combination regimen and suggest that the combination of these clinically relevant agents may represent a new therapeutic option with increased efficacy for patients with GBM.
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Affiliation(s)
- Morrent Thang
- Neuroscience Center, University of North Carolina—Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina—Chapel Hill School of Pharmacy, Chapel Hill, NC, USA
| | - Clara Mellows
- Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina—Chapel Hill School of Pharmacy, Chapel Hill, NC, USA
| | - Lauren E. Kass
- Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina—Chapel Hill School of Pharmacy, Chapel Hill, NC, USA
| | - Sabrina Daglish
- Department of Pharmacology, University of North Carolina—Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Emily M.J. Fennell
- Department of Pharmacology, University of North Carolina—Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Breanna E. Mann
- Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina—Chapel Hill School of Pharmacy, Chapel Hill, NC, USA
| | - Alison R. Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina—Chapel Hill School of Pharmacy, Chapel Hill, NC, USA
| | - Alain Valdivia
- Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina—Chapel Hill School of Pharmacy, Chapel Hill, NC, USA
| | - Lee M. Graves
- Department of Pharmacology, University of North Carolina—Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Shawn D. Hingtgen
- Neuroscience Center, University of North Carolina—Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina—Chapel Hill School of Pharmacy, Chapel Hill, NC, USA
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Groeneveld CS, Sanchez-Quiles V, Dufour F, Shi M, Dingli F, Nicolle R, Chapeaublanc E, Poullet P, Jeffery D, Krucker C, Maillé P, Vacherot F, Vordos D, Benhamou S, Lebret T, Micheau O, Zinovyev A, Loew D, Allory Y, de Reyniès A, Bernard-Pierrot I, Radvanyi F. Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand in FGFR3-mutated Tumors. Eur Urol 2024; 85:483-494. [PMID: 37380559 DOI: 10.1016/j.eururo.2023.05.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/26/2023] [Accepted: 05/26/2023] [Indexed: 06/30/2023]
Abstract
BACKGROUND Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses. OBJECTIVE To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes. DESIGN, SETTING, AND PARTICIPANTS Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available. Four BC-derived cell lines harboring FGFR3 alterations were tested with interventions. INTERVENTION Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), second mitochondrial-derived activator of caspases mimetic (birinapant), pan-FGFR inhibitor (erdafitinib), and FGFR3 knockdown. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Proteomic groups from unsupervised analyses (uPGs) were characterized using clinicopathological, proteomic, genomic, transcriptomic, and pathway enrichment analyses. Additional enrichment analyses were performed for FGFR3-mutated tumors. Treatment effects on cell viability for FGFR3-altered cell lines were evaluated. Synergistic treatment effects were evaluated using the zero interaction potency model. RESULTS AND LIMITATIONS Five uPGs, covering both NMIBC and MIBC, were identified and bore coarse-grained similarity to transcriptomic subtypes underlying common features of these different entities; uPG-E was associated with the Ta pathway and enriched in FGFR3 mutations. Our analyses also highlighted enrichment of proteins involved in apoptosis in FGFR3-mutated tumors, not captured through transcriptomics. Genetic and pharmacological inhibition demonstrated that FGFR3 activation regulates TRAIL receptor expression and sensitizes cells to TRAIL-mediated apoptosis, further increased by combination with birinapant. CONCLUSIONS This proteogenomic study provides a comprehensive resource for investigating NMIBC and MIBC heterogeneity and highlights the potential of TRAIL-induced apoptosis as a treatment option for FGFR3-mutated bladder tumors, warranting a clinical investigation. PATIENT SUMMARY We integrated proteomics, genomics, and transcriptomics to refine molecular classification of bladder cancer, which, combined with clinical and pathological classification, should lead to more appropriate management of patients. Moreover, we identified new biological processes altered in FGFR3-mutated tumors and showed that inducing apoptosis represents a new potential therapeutic option.
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Affiliation(s)
- Clarice S Groeneveld
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Centre de Recherche des Cordeliers, AP-HP, Université Paris Cité, Paris, France
| | - Virginia Sanchez-Quiles
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France
| | - Florent Dufour
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Inovarion, Paris, France
| | - Mingjun Shi
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Florent Dingli
- Centre de Recherche, CurieCoreTech Mass Spectrometry Proteomics, Institut Curie, PSL Research University, Paris, France
| | - Rémy Nicolle
- Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, Université Paris Cité, Paris, France
| | - Elodie Chapeaublanc
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France
| | - Patrick Poullet
- INSERM U900, MINES ParisTech, Institut Curie, PSL Research University, Paris, France
| | - Daniel Jeffery
- Urology Medico-Scientific Program, Department of Translational Research, Institut Curie, PSL Research University, Paris, France
| | - Clémentine Krucker
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France
| | - Pascale Maillé
- Département de Pathologie, Hôpital Henri Mondor, APHP, Créteil, France
| | | | - Dimitri Vordos
- Service d'Urologie, Hôpital Henri Mondor, APHP, Créteil, France
| | | | - Thierry Lebret
- Service d'Urologie, Hôpital Foch, UVSQ, Université Paris-Saclay, Suresnes, France
| | - Olivier Micheau
- INSERM, LNC UMR1231, Université Bourgogne Franche-Comté, Dijon, France
| | - Andrei Zinovyev
- INSERM U900, MINES ParisTech, Institut Curie, PSL Research University, Paris, France
| | - Damarys Loew
- Centre de Recherche, CurieCoreTech Mass Spectrometry Proteomics, Institut Curie, PSL Research University, Paris, France
| | - Yves Allory
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Department of Pathology, Institut Curie, UVSQ, Université Paris-Saclay, Saint-Cloud, France
| | - Aurélien de Reyniès
- Centre de Recherche des Cordeliers, AP-HP, Université Paris Cité, Paris, France
| | - Isabelle Bernard-Pierrot
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France
| | - François Radvanyi
- Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France.
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Zhang G, Xu M, Zhang X, Ma L, Zhang H. TRAIL produced by SAM-1-activated CD4 + and CD8 + subgroup T cells induces apoptosis in human tumor cells through upregulation of death receptors. Toxicol Appl Pharmacol 2021; 427:115656. [PMID: 34329641 DOI: 10.1016/j.taap.2021.115656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/14/2021] [Accepted: 07/24/2021] [Indexed: 10/20/2022]
Abstract
Bacterial superantigens potently activate conventional T-cells to induce massive cytokine production and mediate tumor cell death. To engineer superantigens for immunotherapy against tumors in clinic, we previously generated SAM-1, a staphylococcal enterotoxins C2 (SEC2) mutant, that exhibited significantly reduced toxicity but maintained the superantigen activity in animal models. This present study aimed to investigate whether SAM-1 activates T cells and induces apoptosis in human tumor cells. We found that SAM-1 induced the maturation of dendritic cells (DCs) with upregulating expression of the surface markers CD80, CD86 and HLA-DR, which secreted high levels of IL-12p70 by activating TLR2-NF-κB signaling pathways. SAM-1 could activate human CD4+ subgroup T cells and CD8+ subgroup T cells in the presence of mature dendritic cells (DCs), leading to the productions of cytokines TRAIL, IL-2, IFN-γ and TNF-α. We observed that TRAIL mediated the apoptosis and S-phase and G2/M-phase arrest in HGC-27 tumor cells via binding to upregulated death receptors DR4 and DR5. Using shRNA knockdown in HGC-27 cells or constitutive overexpression in ES2 cells for DR4 and DR5, we demonstrated the vital requirement of DR4 and DR5 in apoptosis of tumor cells in response to TRAIL secreted from SAM-1-activated T cells. Collectively, our results will facilitate better understanding of SAM-1-based immunotherapies for cancer.
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Affiliation(s)
- Guojun Zhang
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Mingkai Xu
- Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, Liaoning, China; Key Laboratory of Superantigen Research, Shenyang Bureau of Science and Technology, Shenyang, Liaoning, China.
| | - Xiaoqing Zhang
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Ling Ma
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Huiwen Zhang
- Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, Liaoning, China
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Potent preclinical activity of HexaBody-DR5/DR5 in relapsed and/or refractory multiple myeloma. Blood Adv 2021; 5:2165-2172. [PMID: 33885752 DOI: 10.1182/bloodadvances.2020003731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/10/2021] [Indexed: 12/23/2022] Open
Abstract
Apoptosis induction by death receptor (DR)-specific agonistic antibodies is a potentially effective antitumor therapy. Nonetheless, to date, all conventional DR-targeting antibodies that induce apoptosis via FcγR-dependent DR clustering failed to show clinical efficacy. HexaBody-DR5/DR5 (GEN1029) has been developed to overcome full FcγR dependence. HexaBody-DR5/DR5 is a mixture of 2 noncompeting DR5-specific immunoglobulin G1 (IgG1) antibodies, each with an E430G mutation in the Fc domain. This mutation enhances Fc-Fc interactions, resulting in antibody hexamerization, followed by FcγR-independent clustering of DR5 molecules. This unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent preclinical antitumor activity in various solid cancers. In this study, we explored the preclinical activity of HexaBody-DR5/DR5 in multiple myeloma (MM), because MM cells are known to express DR5. In bone marrow samples from 48 MM patients, HexaBody-DR5/DR5 induced potent cytotoxicity of primary MM cells. Importantly, HexaBody-DR5/DR5 mediated the highest cytotoxic activity in samples from relapsed/refractory MM patients, including those who are refractory to daratumumab. This improved cytotoxic activity was observed only in patients who received their last anti-MM treatment <1 month ago, suggesting that anti-MM drugs sensitized MM cells to HexaBody-DR5/DR5. Supporting this, bortezomib combined with HexaBody-DR5/DR5 synergistically increased cytotoxicity in MM cells in 7 of 11 newly diagnosed patients. Lenalidomide also synergized with HexaBody-DR5/DR5, but only via its immunomodulatory effects, presumably by enhancing the antibody-dependent cellular cytotoxicity activity of HexaBody-DR5/DR5. Daratumumab showed additive effects when combined with HexaBody-DR5/DR5. In conclusion, the results of this preclinical study indicate a therapeutic potential for HexaBody-DR5/DR5, especially in recently treated relapsed/refractory MM patients.
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García-Martínez JM, Wang S, Weishaeupl C, Wernitznig A, Chetta P, Pinto C, Ho J, Dutcher D, Gorman PN, Kroe-Barrett R, Rinnenthal J, Giragossian C, Impagnatiello MA, Tirapu I, Hilberg F, Kraut N, Pearson M, Kuenkele KP. Selective Tumor Cell Apoptosis and Tumor Regression in CDH17-Positive Colorectal Cancer Models using BI 905711, a Novel Liver-Sparing TRAILR2 Agonist. Mol Cancer Ther 2020; 20:96-108. [PMID: 33037135 DOI: 10.1158/1535-7163.mct-20-0253] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 08/12/2020] [Accepted: 09/30/2020] [Indexed: 11/16/2022]
Abstract
Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages of previous strategies. Here, we show that BI 905711 effectively triggered apoptosis in a broad panel of CDH17-positive colorectal cancer tumor cells in vitro. Efficient induction of apoptosis was dependent on the presence of CDH17, as exemplified by the greater than 1,000-fold drop in potency in CDH17-negative cells. BI 905711 demonstrated single-agent tumor regressions in CDH17-positive colorectal cancer xenografts, an effect that was further enhanced upon combination with irinotecan. Antitumor efficacy correlated with induction of caspase activation, as measured in both the tumor and plasma. Effective tumor growth inhibition was further demonstrated across a series of different colorectal cancer PDX models. BI 905711 induced apoptosis in both a cis (same cell) as well as trans (adjacent cell) fashion, translating into significant antitumor activity even in xenograft models with heterogeneous CDH17 expression. In summary, we demonstrate that BI 905711 has potent and selective antitumor activity in CDH17-positive colorectal cancer models both in vitro and in vivo. The high prevalence of over 95% CDH17-positive tumors in patients with colorectal cancer, the molecule preclinical efficacy together with its potential for a favorable safety profile, support the ongoing BI 905711 phase I trial in colorectal cancer and additional CDH17-positive cancer types (NCT04137289).
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Affiliation(s)
| | - Shirley Wang
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | | | | | - Paolo Chetta
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Catarina Pinto
- Boehringer Ingelheim Cancer Immunology and Immune Modulation, Vienna, Austria
| | - Jason Ho
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Darrin Dutcher
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Philip N Gorman
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Rachel Kroe-Barrett
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Joerg Rinnenthal
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Craig Giragossian
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | | | - Iñigo Tirapu
- Boehringer Ingelheim Cancer Immunology and Immune Modulation, Vienna, Austria
| | - Frank Hilberg
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Norbert Kraut
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Mark Pearson
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
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Thapa B, Kc R, Uludağ H. TRAIL therapy and prospective developments for cancer treatment. J Control Release 2020; 326:335-349. [PMID: 32682900 DOI: 10.1016/j.jconrel.2020.07.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/01/2020] [Accepted: 07/11/2020] [Indexed: 12/22/2022]
Abstract
Tumor Necrosis Factor (TNF) Related Apoptosis-Inducing Ligand (TRAIL), an immune cytokine of TNF-family, has received much attention in late 1990s as a potential cancer therapeutics due to its selective ability to induce apoptosis in cancer cells. TRAIL binds to cell surface death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) and facilitates formation of death-inducing signaling complex (DISC), eventually activating the p53-independent apoptotic cascade. This unique mechanism makes the TRAIL a potential anticancer therapeutic especially for p53-mutated tumors. However, recombinant human TRAIL protein (rhTRAIL) and TRAIL-R agonist monoclonal antibodies (mAb) failed to exert robust anticancer activities due to inherent and/or acquired resistance, poor pharmacokinetics and weak potencies for apoptosis induction. To get TRAIL back on track as a cancer therapeutic, multiple strategies including protein modification, combinatorial approach and TRAIL gene therapy are being extensively explored. These strategies aim to enhance the half-life and bioavailability of TRAIL and synergize with TRAIL action ultimately sensitizing the resistant and non-responsive cells. We summarize emerging strategies for enhanced TRAIL therapy in this review and cover a wide range of recent technologies that will provide impetus to rejuvenate the TRAIL therapeutics in the clinical realm.
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Affiliation(s)
- Bindu Thapa
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
| | - Remant Kc
- Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada.
| | - Hasan Uludağ
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada; Department of Biomedical Engineering, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
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7
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Ke C, Hou H, Li J, Su K, Huang C, Lin Y, Lu Z, Du Z, Tan W, Yuan Z. Extracellular Vesicle Delivery of TRAIL Eradicates Resistant Tumor Growth in Combination with CDK Inhibition by Dinaciclib. Cancers (Basel) 2020; 12:E1157. [PMID: 32375399 PMCID: PMC7281120 DOI: 10.3390/cancers12051157] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/13/2020] [Accepted: 05/01/2020] [Indexed: 12/16/2022] Open
Abstract
Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent that rapidly induces apoptosis in cancer cells. Unfortunately, the clinical application of recombinant TRAIL (rTRAIL) has been hampered by its common cancer resistance. Naturally TRAIL is delivered as a membrane-bound form by extracellular vesicles (EV-T) and is highly efficient for apoptosis induction. SCH727965 (dinaciclib), a potent cyclin-dependent kinase (CDK) inhibitor, was shown to synergize with other drugs to get better efficacy. However, it has never been investigated if dinaciclib coordinates with EV-T to enhance therapeutic results. This study explores the potential of combination therapy with EV-T and dinaciclib for cancer treatment. EV-T was successfully derived from human TRAIL transduced cells and shown to partially overcome resistance of A549 cells. Dinaciclib was shown to drastically enhance EV-T killing effects on cancer lines that express good levels of death receptor (DR) 5, which are associated with suppression of CDK1, CDK9 and anti-apoptotic proteins. Combination therapy with low doses of EV-T and dinaciclib induced strikingly enhanced apoptosis and led to complete regression in A549 tumors without any adverse side effects observed in a subcutaneous xenograft model. Tumor infiltration of mass NK cells and macrophages was also observed. These observations thus indicate that the combination of EV-T with dinaciclib is a potential novel therapy for highly effective and safe cancer treatment.
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Affiliation(s)
- Changhong Ke
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Huan Hou
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Jiayu Li
- School of Industrial Design and Ceramic Art of Foshan University, Foshan 528000 China;
| | - Kui Su
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Chaohong Huang
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Yue Lin
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Zhiqiang Lu
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Zhiyun Du
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Wen Tan
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
| | - Zhengqiang Yuan
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 51006, China; (C.K.); (H.H.); (K.S.); (C.H.); (Y.L.); (Z.L.); (Z.D.); (W.T.)
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Boice A, Bouchier-Hayes L. Targeting apoptotic caspases in cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118688. [PMID: 32087180 DOI: 10.1016/j.bbamcr.2020.118688] [Citation(s) in RCA: 221] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 01/20/2020] [Accepted: 02/15/2020] [Indexed: 12/30/2022]
Abstract
Members of the caspase family of proteases play essential roles in the initiation and execution of apoptosis. These caspases are divided into two groups: the initiator caspases (caspase-2, -8, -9 and -10), which are the first to be activated in response to a signal, and the executioner caspases (caspase-3, -6, and -7) that carry out the demolition phase of apoptosis. Many conventional cancer therapies induce apoptosis to remove the cancer cell by engaging these caspases indirectly. Newer therapeutic applications have been designed, including those that specifically activate individual caspases using gene therapy approaches and small molecules that repress natural inhibitors of caspases already present in the cell. For such approaches to have maximal clinical efficacy, emerging insights into non-apoptotic roles of these caspases need to be considered. This review will discuss the roles of caspases as safeguards against cancer in the context of the advantages and potential limitations of targeting apoptotic caspases for the treatment of cancer.
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Affiliation(s)
- Ashley Boice
- Department of Pediatrics, Division of Hematology-Oncology and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA
| | - Lisa Bouchier-Hayes
- Department of Pediatrics, Division of Hematology-Oncology and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.
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Wang J, Li Y, Sun W, Liu J, Chen W. Synergistic effects of rmhTRAIL and 17-AAG on the proliferation and apoptosis of multiple myeloma cells. ACTA ACUST UNITED AC 2018; 23:620-625. [PMID: 29566599 DOI: 10.1080/10245332.2018.1449338] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
OBJECTIVE This study aimed to investigate synergistic effects of recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmhTRAIL) and heat-shock protein 90 (HSP90) inhibitor (geldanamycin derivative 17 -allylamino- 17-demethoxy -geldanamycin, 17-AAG) on the proliferation and apoptosis of multiple myeloma (MM) cells. METHODS MTT assays evaluated inhibitory effects of rmhTRAIL and 17-AAG in different concentrations and treatment durations on the proliferation of RPMI8226 and U266 cells. The half maximal inhibitory concentration was calculated using OriginPro7.5. Synergistic effects of rmhTRAIL and 17-AAG on apoptosis of MM cells were detected using flow cytometry at 24 and 48 h post-treatment. To evaluate synergistic effects of rmhTRAIL and 17-AAG, the Q-value was calculated using King's formula. RESULTS rmhTRAIL exhibited significant inhibitory effects on the proliferation of RPMI8226 cells in a dose- and time-dependent manner (>50%), whereas U266 cells were not sensitive to rmhTRAIL (<50%). 17-AAG inhibited the proliferation of RPMI8226 and U266 cells in a dose-dependent manner (>80%). Significant synergistic effects of rmhTRAIL and 17-AAG on the proliferation of RPMI8226 cells were revealed (Q-value > 1.15), whereas synergistic effects were not evident on the proliferation of U266 cells (Q-value < 1.15). rmhTRAIL and 17-AAG exhibited significant synergistic effects on apoptosis of RPMI8226 and U266 cells (Q-value > 1.15). CONCLUSION The combined application of rmhTRAIL and 17-AAG revealed favorable synergistic effects in the treatment of MM.
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Affiliation(s)
- Jing Wang
- a Department of hematology , Daqing oil-field general hospital , Daqing City , China
| | - Yun Li
- a Department of hematology , Daqing oil-field general hospital , Daqing City , China
| | - Wei Sun
- b Department of infectation , Daqing oil-field general hospital , Daqing City , China
| | - Jing Liu
- a Department of hematology , Daqing oil-field general hospital , Daqing City , China
| | - Wenming Chen
- c Department of hematology , Beijing Chao-yang hospital , Beijing , China
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10
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Mesenchymal stem cells expressing osteoprotegerin variants inhibit osteolysis in a murine model of multiple myeloma. Blood Adv 2017; 1:2375-2385. [PMID: 29296887 DOI: 10.1182/bloodadvances.2017007310] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 10/25/2017] [Indexed: 12/26/2022] Open
Abstract
The current treatment options for multiple myeloma (MM) osteolytic lesions are mainly combinations of chemotherapy and other small-molecule inhibitors, but toxic side effects still remain a major concern. Studies have shown that osteoclast activity is enhanced in MM patients through increased expression of receptor activator of nuclear factor κB ligand (RANKL), triggering RANK signaling on osteoclast precursors, which results in aggressive bone resorption. Furthermore, osteoprotegerin (OPG), a decoy receptor for RANKL, and the osteogenic potential of mesenchymal stem cells (MSCs) are significantly decreased in myeloma patients with multiple bone lesions. Thus, the use of OPG as a therapeutic molecule would greatly decrease osteolytic damage and reduce morbidity. However, in addition to inhibiting osteoclast activation, OPG binds to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), thereby rendering the tumor cells resistant to TRAIL-induced apoptosis and limiting the use of OPG for therapy. The present study developed a bone-disseminated myeloma disease model in mouse and successfully tested a cell therapy approach using MSCs, genetically engineered to express OPG variants that retain the capacity to bind RANKL, but do not bind TRAIL. Our results of skeletal remodeling following this regenerative stem cell therapy with OPG variants indicated a significant protection against myeloma-induced osteolytic bone damage in areas of major myeloma skeletal dissemination, suggesting the potential of this therapy for treating osteolytic damage in myeloma patients.
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11
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Wagner JA, Rosario M, Romee R, Berrien-Elliott MM, Schneider SE, Leong JW, Sullivan RP, Jewell BA, Becker-Hapak M, Schappe T, Abdel-Latif S, Ireland AR, Jaishankar D, King JA, Vij R, Clement D, Goodridge J, Malmberg KJ, Wong HC, Fehniger TA. CD56bright NK cells exhibit potent antitumor responses following IL-15 priming. J Clin Invest 2017; 127:4042-4058. [PMID: 28972539 DOI: 10.1172/jci90387] [Citation(s) in RCA: 216] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 08/15/2017] [Indexed: 12/12/2022] Open
Abstract
NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.
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Affiliation(s)
- Julia A Wagner
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maximillian Rosario
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Rizwan Romee
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Melissa M Berrien-Elliott
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Stephanie E Schneider
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jeffrey W Leong
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Ryan P Sullivan
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Brea A Jewell
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Michelle Becker-Hapak
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Timothy Schappe
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Sara Abdel-Latif
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Aaron R Ireland
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Devika Jaishankar
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Justin A King
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Ravi Vij
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Dennis Clement
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.,The KG Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jodie Goodridge
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway
| | - Karl-Johan Malmberg
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.,The KG Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | | | - Todd A Fehniger
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
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12
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Huang Y, Li X, Sha H, Zhang L, Bian X, Han X, Liu B. sTRAIL-iRGD is a promising therapeutic agent for gastric cancer treatment. Sci Rep 2017; 7:579. [PMID: 28373646 PMCID: PMC5428854 DOI: 10.1038/s41598-017-00688-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 03/08/2017] [Indexed: 12/21/2022] Open
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells and augments chemotherapeutics in vivo. Here, we developed sTRAIL-iRGD, a recombinant protein consisting of sTRAIL fused to CRGDKGPDC, a C-terminal end binding peptide with an integrin-binding arginine-glycine-aspartic acid (iRGD) motif. CRGDKGPDC is a tumor-homing peptide with high penetration into tumor tissue and cells. We found that sTRAIL-iRGD internalized into cultured gastric cancer tumor cells and localized to both the tumor mass in vivo and three-dimensional multicellular spheroids in vitro. sTRAIL-iRGD had an antitumor effect in tumor cell lines, multicellular spheroids and nude mice with tumors. Repeated treatment with sTRAIL-iRGD reduced tumor growth and volume in vivo. Mice treated with sTRAIL-iRGD and paclitaxel (PTX) in combination showed no sign of sTRAIL-iRGD-related liver toxicity. Our data suggest that sTRAIL-iRGD is a promising anti-gastric cancer agent with high selectivity and limited systemic toxicity.
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Affiliation(s)
- Ying Huang
- Department of Pain of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xihan Li
- Central Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated Nanjing University of Chinese Medicine, Nanjing, China
| | - Huizi Sha
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, China
| | - Lianru Zhang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, China
| | - Xinyu Bian
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, China.
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13
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Guillaume YC, André C. Comparative binding to DR4 and DR5 receptors of TRAIL and BNNTs/PAHE/mPEG-DSPE/TRAIL nanoparticles. J Mol Recognit 2017; 30. [PMID: 28120533 DOI: 10.1002/jmr.2611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 12/15/2016] [Accepted: 01/02/2017] [Indexed: 12/19/2022]
Abstract
TRAIL is a member of the tumor necrosis factor family of cytokines, which induces apoptosis of cancer cells, thanks to its binding to its cognate receptors DR5 and DR4. We have recently demonstrated that nanovectorization of TRAIL with single-walled carbon nanotubes enhanced TRAIL affinity to DR5. In this paper, 1-pyrenebutyric acid N-hydroxysuccinimide ester functionalized boron nitride nanotubes (BNNTs) were used to anchor the TRAIL protein. The resulting BNNT/1-pyrenebutyric acid N-hydroxysuccinimide ester nanotubes were mixed with methoxy-poly(ethylene glycol)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-conjugates so as to allow a good dispersion of these nanoparticle TRAIL (NPT) in aqueous solution. The difference of binding between NPT and soluble TRAIL to DR4 and DR5 receptors was then studied by the use of affinity chromatography. DR4 and DR5 receptors were thus immobilized on a chromatographic support, and the binding of the 2 ligands TRAIL and NPT to DR4 and DR5 was studied in the temperature range 30°C to 50°C. Negative enthalpy (ΔH) values indicated that van der Waals interactions and hydrogen bonding are engaged favorably at the ligand-receptor interface. It was shown that their rank-ordered affinities were strongly different in the sequence TRAILDR4 < NPTDR4 < TRAILDR5 < NPTDR5 , and the highest affinity for NPT to DR4 and DR5 receptors observed at low pHs was due to the less accessibility of the His molecular switch to be protonated when TRAIL was immobilized on BNNTs. Taken together, our results demonstrated that nanovectorization of TRAIL with BNNTs enhanced its binding to both DR4 and DR5 receptors at 37°C. Our novel nanovector could potentially be used for delivering TRAIL to cells for cancer treatment.
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Affiliation(s)
- Yves Claude Guillaume
- University of Franche-Comté, Besançon, France.,EA481 Neurosciences Intégratives et Cliniques/Pôle Chimie Analytique Bioanalytique et Physique (PNCABP), Besançon, France.,CHRU Besançon, Pôle Pharmaceutique, Besançon, France
| | - Claire André
- University of Franche-Comté, Besançon, France.,EA481 Neurosciences Intégratives et Cliniques/Pôle Chimie Analytique Bioanalytique et Physique (PNCABP), Besançon, France.,CHRU Besançon, Pôle Pharmaceutique, Besançon, France
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14
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Guillaume YC, Lethier L, André C. An HPLC method associated with a thermodynamic analysis to compare the binding of TRAIL and its nanovectorized form to death receptors DR4 and DR5 and their relationship to cytotoxicity. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1036-1037:142-148. [DOI: 10.1016/j.jchromb.2016.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 09/27/2016] [Accepted: 10/10/2016] [Indexed: 12/24/2022]
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15
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Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway. Oncogene 2016; 36:1417-1429. [PMID: 27641334 PMCID: PMC5346295 DOI: 10.1038/onc.2016.309] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 07/01/2016] [Accepted: 07/19/2016] [Indexed: 12/21/2022]
Abstract
Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug resistance in multiple myeloma.
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16
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Anees M, Horak P, Schiefer AI, Vaňhara P, El-Gazzar A, Perco P, Kiesewetter B, Müllauer L, Streubel B, Raderer M, Krainer M. The potential evasion of immune surveillance in mucosa associated lymphoid tissue lymphoma by DcR2-mediated up-regulation of nuclear factor-κB. Leuk Lymphoma 2014; 56:1440-9. [PMID: 25248880 DOI: 10.3109/10428194.2014.953149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
This study investigated expression profiles of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) pathway components and mechanisms underlying TRAIL-induced apoptosis in mucosa associated lymphoid tissue (MALT) lymphoma. Genetic aberrations including translocations and trisomies were assessed by reverse transcription polymerase chain reaction and fluorescence in situ hybridization. Expression of TRAIL, death receptors 4 and 5, decoy receptors 1 and 2, and FADD-like interleukin-1β-converting enzyme (FLICE) inhibitory protein was analyzed by immunohistochemistry. All 32 patients under study showed some alterations in TRAIL pathway mainly involving loss of death receptors (37.5%), gain of decoy receptors (3.1%) or both (59.4%). Decoy receptor 2 (DcR2) was highly expressed in patients with normal cytogenetic status as compared to those with cytogenetic aberrations (p = 0.005). Moreover, DcR2 expression correlated significantly with nuclear factor-κB (NF-κB) expression (R = 0.372, p = 0.047). High expression of DcR2 in patients with normal cytogenetic status and its significant correlation with NF-κB expression provides a potential clue to evasion of immune surveillance in cytogenetically normal MALT lymphomas.
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Affiliation(s)
- Mariam Anees
- Division of Oncology, Department of Medicine I, Medical University of Vienna , Vienna , Austria
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17
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Koschny R, Boehm C, Sprick MR, Haas TL, Holland H, Xu LX, Krupp W, Mueller WC, Bauer M, Koschny T, Keller M, Sinn P, Meixensberger J, Walczak H, Ganten TM. Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex. J Neuropathol Exp Neurol 2014; 73:1034-46. [PMID: 25289891 DOI: 10.1097/nen.0000000000000129] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.
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Affiliation(s)
- Ronald Koschny
- From the Department of Gastroenterology, Heidelberg University Hospital (RK, TMG); German Cancer Research Center, Division of Signaling and Functional Genomics (CB); Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University (CB); and HI-STEM gGmbH/German Cancer Research Center Heidelberg (MRS), Heidelberg, Germany; National Cancer Institute Regina Elena (TLH), Rome, Italy; Translational Centre for Regenerative Medicine Leipzig and Faculty of Medicine (HH, L-XX) and Departments of Neurosurgery (L-XX, WK, JM) and Neuropathology (WCM, MB), University of Leipzig, Leipzig, Germany; Ames Laboratory-US DOE, and Department of Physics and Astronomy, Iowa State University, Ames, Iowa (TK); Departments of Cardiology (MK) and Pathology (PS), University Hospital Heidelberg, Heidelberg, Germany; and Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, London, United Kingdom (HW)
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18
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Graves JD, Kordich JJ, Huang TH, Piasecki J, Bush TL, Sullivan T, Foltz IN, Chang W, Douangpanya H, Dang T, O'Neill JW, Mallari R, Zhao X, Branstetter DG, Rossi JM, Long AM, Huang X, Holland PM. Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperate to promote receptor clustering and antitumor activity. Cancer Cell 2014; 26:177-89. [PMID: 25043603 DOI: 10.1016/j.ccr.2014.04.028] [Citation(s) in RCA: 131] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 02/28/2014] [Accepted: 04/30/2014] [Indexed: 12/15/2022]
Abstract
Death receptor agonist therapies have exhibited limited clinical benefit to date. Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG 655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure determination of the Apo2L/TRAIL-DR5-AMG 655 ternary complex illustrates how higher order clustering of DR5 is achieved when both agents are combined. Enhanced agonism generated by combining Apo2L/TRAIL and AMG 655 provides insight into the limited efficacy observed in previous clinical trials and suggests testable hypotheses to reconsider death receptor agonism as a therapeutic strategy.
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MESH Headings
- Animals
- Antibodies, Monoclonal/chemistry
- Antibodies, Monoclonal/pharmacology
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Cell Line, Tumor
- Cell Survival
- Crystallography, X-Ray
- Drug Resistance, Neoplasm
- Drug Synergism
- Humans
- Mice
- Models, Molecular
- Protein Multimerization
- Protein Structure, Quaternary
- Receptors, TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitors
- Receptors, TNF-Related Apoptosis-Inducing Ligand/chemistry
- Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
- Signal Transduction
- TNF-Related Apoptosis-Inducing Ligand/chemistry
- TNF-Related Apoptosis-Inducing Ligand/pharmacology
- Xenograft Model Antitumor Assays
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Affiliation(s)
| | | | - Tzu-Hsuan Huang
- Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA
| | - Julia Piasecki
- Therapeutic Innovation Unit, Amgen Inc., Seattle, WA 98119, USA
| | - Tammy L Bush
- Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA
| | - Timothy Sullivan
- Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA
| | - Ian N Foltz
- Department of Biologic Discovery, Amgen British Columbia, Burnaby, BC V5A 1V7, Canada
| | - Wesley Chang
- Department of Clinical Immunology, Amgen Inc., South San Francisco, CA 94080, USA
| | | | - Thu Dang
- Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA
| | - Jason W O'Neill
- Department of Biologic Optimization, Amgen Inc., Seattle, WA 98119, USA
| | - Rommel Mallari
- Department of Molecular Structure and Characterization, Amgen, South San Francisco, CA, 94080, USA
| | - Xiaoning Zhao
- Department of Molecular Structure and Characterization, Amgen, South San Francisco, CA, 94080, USA
| | | | - John M Rossi
- Department of Molecular Sciences and Computational Biology, Amgen Inc., Thousand Oaks, CA 91320, USA
| | - Alexander M Long
- Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, MA 02142, USA
| | - Xin Huang
- Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, MA 02142, USA
| | - Pamela M Holland
- Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA.
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19
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Loi M, Becherini P, Emionite L, Giacomini A, Cossu I, Destefanis E, Brignole C, Di Paolo D, Piaggio F, Perri P, Cilli M, Pastorino F, Ponzoni M. sTRAIL coupled to liposomes improves its pharmacokinetic profile and overcomes neuroblastoma tumour resistance in combination with Bortezomib. J Control Release 2014; 192:157-66. [PMID: 25041999 DOI: 10.1016/j.jconrel.2014.07.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 07/08/2014] [Accepted: 07/10/2014] [Indexed: 01/26/2023]
Abstract
Neuroblastoma (NB), the most common and deadly extracranial solid tumour of childhood, represents a challenging in paediatric oncology. Soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) is a cancer cell-specific molecule exerting remarkable anti-tumour activities against paediatric malignancies both in vitro and in preclinical settings. However, due to its too fast elimination and to the undesired related side effects, the improvement of sTRAIL in vivo bioavailability and the specific delivery to the tumour is mandatory for increasing its therapeutic efficacy. In this manuscript, we developed an innovative pegylated liposomal formulation carrying the sTRAIL at the outer surface (sTRAIL-SL) with the intent to improve its serum half-life and increase its efficacy in vivo, while reducing side effects. Furthermore, the possibility to combine sTRAIL-SL with the proteasome inhibitor Bortezomib (BTZ) was investigated, being BTZ able to sensitize tumour cells toward TRAIL-induced apoptosis. We demonstrated that sTRAIL preserved and improved its anti-tumour activity when coupled to nanocarriers. Moreover, sTRAIL-SL ameliorated its PK profile in blood allowing sTRAIL to exert a more potent anti-tumour activity, which led, upon BTZ priming, to a statistically significant enhanced life spans in two models of sTRAIL-resistant NB-bearing mice. Finally, mechanistic studies indicated that the combination of sTRAIL with BTZ sensitized sTRAIL-resistant NB tumour cells to sTRAIL-induced cell death, both in vitro and in vivo, through the Akt/GSK3/β-catenin axis-dependent mechanism. In conclusion, our results suggest that sTRAIL-SL might be an efficient vehicle for sTRAIL delivery and that its use in clinic, in combination with BTZ, might represent an adjuvant strategy for the treatment of stage IV, sTRAIL-resistant, NB patients.
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Affiliation(s)
- M Loi
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - P Becherini
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - L Emionite
- Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - A Giacomini
- Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Italy
| | - I Cossu
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - E Destefanis
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - C Brignole
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - D Di Paolo
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - F Piaggio
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - P Perri
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy
| | - M Cilli
- Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - F Pastorino
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
| | - M Ponzoni
- Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
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20
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Bosman MCJ, Reis CR, Schuringa JJ, Vellenga E, Quax WJ. Decreased affinity of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) D269H/E195R to osteoprotegerin (OPG) overcomes TRAIL resistance mediated by the bone microenvironment. J Biol Chem 2013; 289:1071-8. [PMID: 24280212 DOI: 10.1074/jbc.m113.491589] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The bone marrow microenvironment provides important signals for the survival and proliferation of hematopoietic and malignant cells. In multiple myeloma, plasma cells are surrounded by stromal cells including osteoblasts. These stromal cells protect multiple myeloma cells from apoptosis induced by chemotherapeutic agents. Osteoprotegerin (OPG), a soluble receptor of the cytokine TNF-related apoptosis-inducing ligand (TRAIL), is secreted by osteoblasts and has been implicated in the prevention of cell death induced by TRAIL in malignant cells. Previously, we have designed death receptor-specific TRAIL variants that induce apoptosis exclusively via one of its death receptors. Here, we have studied in detail the interaction between recombinant human (rhTRAIL) variants and OPG. We show that a DR5-specific variant (rhTRAIL D269H/E195R) displays a significantly decreased affinity to OPG. Furthermore, this rhTRAIL variant shows a much higher activity when compared with rhTRAIL WT and retains its effectiveness in inducing cell death in multiple myeloma cell lines, in the presence of OPG secreted by stromal cells. We also demonstrate that stromal cells are largely insensitive to high concentrations of this rhTRAIL variant. In conclusion, rhTRAIL D269H/E195R is a potential therapy for multiple myeloma due to its high effectiveness and diminished binding to OPG.
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Affiliation(s)
- Matthieu C J Bosman
- From the Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen and
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Evaluation of TNF superfamily molecules in multiple myeloma patients: Correlation with biological and clinical features. Leuk Res 2013; 37:1089-93. [DOI: 10.1016/j.leukres.2013.05.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Revised: 04/13/2013] [Accepted: 05/18/2013] [Indexed: 01/14/2023]
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Abstract
Despite the significant advances in clinical research, surgical resection, radiotherapy and chemotherapy are still used as the primary method for cancer treatment. As compared to conventional therapies that often induce systemic toxicity and eventually contribute to tumor resistance, the TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that selectively triggers apoptosis in various cancer cells by interacting with its proapoptotic receptors DR4 and KILLER/DR5, while sparing the normal surrounding tissue. The intensive studies of TRAIL signaling pathways over the past decade have provided clues for understanding the molecular mechanisms of TRAIL-induced apoptosis in carcinogenesis and identified an array of therapeutic responses elicited by TRAIL and its receptor agonists. Analysis of its activity at the molecular level has shown that TRAIL improves survival either as monotherapies or combinatorial therapies with other mediators of apoptosis or anticancer chemotherapy. Combinatorial treatments amplify the activities of anticancer agents and widen the therapeutic window by overcoming tumor resistance to apoptosis and driving cancer cells to self-destruction. Although TRAIL sensitivity varies widely depending on the cell type, nontransformed cells are largely resistant to death mediated by TRAIL Death Receptors (DRs). Genetic alterations in cancer can contribute in tumor progression and often play an important role in evasion of apoptosis by tumor cells. Remarkably, RAS, MYC and HER2 oncogenes have been shown to sensitise tumor cells to TRAIL induced cell death. Here, we summarise the cross-talk of oncogenic and apoptotic pathways and how they can be exploited toward efficient combinatorial therapeutic protocols.
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Affiliation(s)
- Eftychia Oikonomou
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48, Vasileos Konstantinou Ave., 11635, Athens, Greece
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Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A, Ford HL. On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene 2013; 32:1341-50. [PMID: 22580613 PMCID: PMC4502956 DOI: 10.1038/onc.2012.164] [Citation(s) in RCA: 224] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Revised: 03/19/2012] [Accepted: 03/21/2012] [Indexed: 12/11/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL-based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance, and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL-based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL DRs in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.
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Affiliation(s)
- L Y Dimberg
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA
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Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro. Apoptosis 2012; 17:121-31. [PMID: 21972115 DOI: 10.1007/s10495-011-0662-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
TRAIL (TNF-related apoptosis-inducing ligand) has been shown to induce apoptosis by binding to TRAIL-R1 and -R2 death receptors, but not to TRAIL-R3 or -R4, its decoy receptors that lack the internal death domain. Osteoclasts (Ocs) are sensitive to TRAIL-induced apoptosis, and modulation of these receptors may change Oc sensitivity to TRAIL. Using human Oc cultures, we first investigated the gene expression profile of these receptors (TNFRSF10 -A, -B, -C, -D encoding TRAIL-Rs 1-4) by real time PCR after adding osteotropic factors during the last week of Oc cultures. We observed a significant decrease in the expression of TNFRSF10-A after the addition of TGFβ, and an increase in that of TNFRSF10-A and -B post-PTH stimulation. Protein expression of TRAIL-R1 and -R3 was upregulated in the presence of MIP-1α, but down-regulated in the presence of TGFβ (R1), TRAIL (R2) or OPG (R3). The percentage of Ocs expressing the TRAIL-R1 and/or -R2 at their surface was increased by MIP-1α and TRAIL, increased (R2) or decreased (R1) by TGFβ, and the percentage expressing TRAIL-R3 was increased by MIP-1α, TRAIL and RANKL. Although significant, the magnitude of all these changes was of about 10-15%. While a direct correlation between these changes and TRAIL-induced Oc apoptosis was less clear, a protective effect was observed in Ocs that had been treated with OPG, and an additive effect in Ocs pre-treated with TRAIL or TGFβ increased TRAIL sensitivity.
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Vitovski S, Chantry AD, Lawson MA, Croucher PI. Targeting tumour-initiating cells with TRAIL based combination therapy ensures complete and lasting eradication of multiple myeloma tumours in vivo. PLoS One 2012; 7:e35830. [PMID: 22615740 PMCID: PMC3353958 DOI: 10.1371/journal.pone.0035830] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Accepted: 03/26/2012] [Indexed: 11/22/2022] Open
Abstract
Multiple myeloma (MM) remains an incurable disease despite improvements to available treatments and efforts to identify new drug targets. Consequently new approaches are urgently required. We have investigated the potential of native tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with doxorubicin, to induce apoptotic cell death in phenotypically distinct populations of myeloma cells in vitro and in vivo. The cytotoxic potential of TRAIL alone, and in combination with DOX, was assessed in vitro in purified CD138(+) and CD138(-) cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD138(-) MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD138(-) cells were shown to be more resistant to the cytotoxic activity of TRAIL than CD138(+) cells and have reduced expression of TRAIL death receptors. This resistance results in preferential killing of CD 138(+) cells during exposure of MM culture to TRAIL. Furthermore, prolonged exposure results in the appearance of TRAIL-resistant CD138(-) cells. However, when TRAIL is combined with doxorubicin, this results in complete eradication of MM cells in vivo. Most importantly, this treatment successfully eliminates CD138(-) cells implicated in tumour initiation and growth maintenance. These findings may explain the failure of current therapies and offer a promising new approach in the quest to cure MM and disseminated cancers.
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Affiliation(s)
- Srdjan Vitovski
- The Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
- Department of Infection and Immunity, The Medical School, Sheffield, United Kingdom
| | - Andrew D. Chantry
- The Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Michelle A. Lawson
- The Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Peter I. Croucher
- The Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
- Garvan Institute for Medical Research, Sydney, Australia
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Ciavarella S, Grisendi G, Dominici M, Tucci M, Brunetti O, Dammacco F, Silvestris F. In vitro anti-myeloma activity of TRAIL-expressing adipose-derived mesenchymal stem cells. Br J Haematol 2012; 157:586-98. [DOI: 10.1111/j.1365-2141.2012.09082.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 01/30/2012] [Indexed: 01/14/2023]
Affiliation(s)
- Sabino Ciavarella
- Department of Internal Medicine and Oncology (DIMO); University of Bari ‘A. Moro’; Bari
| | - Giulia Grisendi
- Department of Oncology, Haematology and Respiratory Diseases; University-Hospital of Modena and Reggio Emilia; Modena; Italy
| | - Massimo Dominici
- Department of Oncology, Haematology and Respiratory Diseases; University-Hospital of Modena and Reggio Emilia; Modena; Italy
| | - Marco Tucci
- Department of Internal Medicine and Oncology (DIMO); University of Bari ‘A. Moro’; Bari
| | - Oronzo Brunetti
- Department of Internal Medicine and Oncology (DIMO); University of Bari ‘A. Moro’; Bari
| | - Franco Dammacco
- Department of Internal Medicine and Oncology (DIMO); University of Bari ‘A. Moro’; Bari
| | - Franco Silvestris
- Department of Internal Medicine and Oncology (DIMO); University of Bari ‘A. Moro’; Bari
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Tumor necrosis factor-related apoptosis-inducing ligand expression correlates to temporomandibular joint disk degeneration. J Craniofac Surg 2011; 22:504-8. [PMID: 21403533 DOI: 10.1097/scs.0b013e3182087394] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
This study investigated if tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) immunohistochemical expression in human temporomandibular joint (TMJ)-degenerated disks correlates to the degree of tissue damage to elucidate the possible involvement of this apoptotic pathway in TMJ disk degeneration. Twenty-one TMJ displaced disk from 12 patients were affected by anterior disk displacement with reduction and 9 by anterior disk displacement without reduction processed immunohistochemically with TRAIL antibody. Histopathologic grading of the disk degeneration was carried out in each specimen. The mean histopathologic score of the TMJ degenerated disks was 4.77±1.26 (minimum, 2; maximum, 7). Immunolabeling for TRAIL was detected in the cytoplasm of the TMJ disk cells in every sample, although with different patterns of reactivity. The degree of TRAIL immunostaining was correlated to the histopathologic degeneration score obtained from the sample (Spearman ρ=0.617). Therefore, cell loss due to the involvement of TRAIL apoptotic pathway seems, in part, responsible for TMJ disk degeneration.
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Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma. Br J Cancer 2011; 104:957-67. [PMID: 21364585 PMCID: PMC3065279 DOI: 10.1038/bjc.2011.42] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: Although inhibitors of histone deacetylase inhibitors (HDACis) in combination with genotoxins potentiate apoptosis, the role of proteases other than caspases in this process remained elusive. Therefore, we examined the potentiation of apoptosis and related mechanisms of HDACis and doxorubicin combination in a panel of myeloma cell lines and in 25 primary myelomas. Results: At IC50 concentrations, sodium butyrate (an HDACi) or doxorubicin alone caused little apoptosis. However, their combination potentiated apoptosis and synergistically reduced the viability of myeloma cells independent of p53 and caspase 3–7 activation. Potentiated apoptosis correlated with nuclear translocation of apoptosis-inducing factor, suggesting the induction of caspase 3- and 7-independent pathways. Consistent with this, butyrate and doxorubicin combination significantly increased the activity of cytoplasmic cathepsin B. Inhibition of cathepsin B either with a small-molecule inhibitor or downregulation with a siRNA reversed butyrate- and doxorubicin-potentiated apoptosis. Finally, ex vivo, clinically relevant concentrations of butyrate or SAHA (suberoylanilide hydroxamic acid, vorinostat, an HDACi in clinical testing) in combination with doxorubicin significantly (P<0.0001) reduced the survival of primary myeloma cells. Conclusions: Cathepsin B has a prominent function in mediating apoptosis potentiated by HDACi and doxorubicin combinations in myeloma. Our results support a molecular model of lysosomal–mitochondrial crosstalk in HDACi- and doxorubicin-potentiated apoptosis through the activation of cathepsin B.
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Feng X, Yan J, Wang Y, Zierath JR, Nordenskjöld M, Henter JI, Fadeel B, Zheng C. The proteasome inhibitor bortezomib disrupts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and natural killer (NK) cell killing of TRAIL receptor-positive multiple myeloma cells. Mol Immunol 2010; 47:2388-96. [PMID: 20542572 DOI: 10.1016/j.molimm.2010.05.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2010] [Accepted: 05/05/2010] [Indexed: 11/29/2022]
Abstract
Bortezomib, a potent 26S proteasome inhibitor, is approved for the treatment of multiple myeloma (MM) and clinical trials are under way to evaluate its efficacy in other malignant diseases. However, cytotoxic effects of bortezomib on immune-competent cells have also been observed. In this study, we show that bortezomib downregulates cell surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on primary human interleukin (IL)-2-activated natural killer (NK) cells. Pharmacological inhibition of the transcription factor, NF-kappaB also profoundly decreased TRAIL expression, suggesting that NF-kappaB is involved in the regulation of TRAIL expression in activated human NK cells. Furthermore, perforin-independent killing of the human MM cell lines RPMI8226 and U266 by NK cells was markedly suppressed following bortezomib treatment. In addition, blocking cell surface-bound TRAIL with a TRAIL antibody impaired NK cell-mediated lysis of the TRAIL-sensitive MM cell line, RPMI8226. In conclusion, the proteasome is likely to be involved in the regulation of TRAIL expression in primary human IL-2-activated NK cells. Proteasome inhibition by bortezomib disrupts TRAIL expression and TRAIL dependent and/or independent pathway-mediated killing of myeloma cells, suggesting that bortezomib may potentially hamper NK-dependent immunosurveillance against tumors in patients treated with this drug.
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Affiliation(s)
- Xiaoli Feng
- Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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Berg D, Stühmer T, Siegmund D, Müller N, Giner T, Dittrich-Breiholz O, Kracht M, Bargou R, Wajant H. Oligomerized tumor necrosis factor-related apoptosis inducing ligand strongly induces cell death in myeloma cells, but also activates proinflammatory signaling pathways. FEBS J 2009; 276:6912-27. [PMID: 19895579 DOI: 10.1111/j.1742-4658.2009.07388.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The oligomerization status of soluble tumor necrosis factor-related apoptosis inducing ligand (TRAIL) trimers has an overwhelming impact on cell death induction in a cell-type dependent fashion. Thus, we evaluated the ability of single and oligomerized TRAIL trimers to induce cell death in human myeloma cells. In all myeloma cell lines analyzed, oligomerized TRAIL trimers induced caspase activation and complete cell death, whereas non-oligomerized TRAIL trimers showed no or only a modest effect. Caspase activation induced by oligomerized TRAIL was blocked in all cell lines by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk). Cell death induction was largely blocked in two cell lines by z-VAD-fmk, but was only marginally attenuated in three other cell lines, indicating that TRAIL induces caspase-dependent and caspase-independent cell death in myeloma cells. Preceding cell death, TRAIL activated nuclear factor kappaB, c-Jun N-terminal kinase, p38 and p42/44. Although TRAIL-induced stimulation of c-Jun N-terminal kinase and p38 was caspase-dependent in a cell type-specific fashion, activation of nuclear factor kappaB and p42/44 was caspase-independent in all cases. In accordance with activation of the nuclear factor kappaB pathway, we observed transcriptional up-regulation of several well established nuclear factor kappaB target genes. Furthermore, we found that TRAIL activates proinflammatory pathways in approximately 50% of primary myeloma samples. Taken together, our data suggest (a) that oligomerized TRAIL variants are necessary to ensure maximal cell death induction in myeloma cells and (b) TRAIL should be used in combination with anti-inflammatory drugs for treatment of myeloma to avoid and/or minimize any potential side-effects arising from the proinflammatory properties of the molecule.
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Affiliation(s)
- Daniela Berg
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Germany
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Corallini F, Milani D, Nicolin V, Secchiero P. TRAIL, caspases and maturation of normal and leukemic myeloid precursors. Leuk Lymphoma 2009; 47:1459-68. [PMID: 16966254 DOI: 10.1080/10428190500513611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a membrane-bound cytokine molecule that belongs to the family of tumor necrosis factor (TNF). Members of this family share diverse biological effects, including induction of apoptosis and/or promotion of cell survival. Identification of TRAIL has generated considerable enthusiasm for its ability to induce apoptotic cell death in a variety of tumor cells, by engaging the death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5, while sparing most normal cells. Beside its anticancer activity, several studies have suggested a role for endogenously expressed TRAIL in hemopoiesis. In this review, we summarize the knowledge about the different lineage-specific roles of TRAIL and its receptors in hemopoiesis regulation. Moreover, the complex interplay among the signaling pathways triggered by TRAIL/TRAIL-receptors in myeloid cells is discussed in some detail.
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Affiliation(s)
- Federica Corallini
- Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara 66, 44100, Ferrara, Italy
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Balsas P, López-Royuela N, Galán-Malo P, Anel A, Marzo I, Naval J. Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis. Biochem Pharmacol 2008; 77:804-12. [PMID: 19100720 DOI: 10.1016/j.bcp.2008.11.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2008] [Revised: 11/13/2008] [Accepted: 11/14/2008] [Indexed: 11/18/2022]
Abstract
The proteasome inhibitor bortezomib is currently an important drug for treatment of relapsed and refractory multiple myeloma (MM) and for elderly patients. However, cells from some patients show resistance to bortezomib. We have evaluated the possibility of improving bortezomib therapy with Apo2L/TRAIL, a death ligand that induces apoptosis in MM but not in normal cells. Results indicate that cotreatment with low doses of bortezomib significantly increased apoptosis of MM cells showing partial sensitivity to Apo2L/TRAIL. Bortezomib treatment did not significantly alter plasma membrane amount of DR4 and DR5 but increased Apo2L/TRAIL-induced caspase-8 and caspase-3 activation. Apo2L/TRAIL reverted bortezomib-induced up-regulation of beta-catenin, Mcl-1 and FLIP, associated with the enhanced cytotoxicity of combined treatment. More important, some cell lines displaying resistance to bortezomib were sensitive to Apo2L/TRAIL-induced apoptosis. A cell line made resistant by continuous culture of RPMI 8226 cells in the presence of bortezomib (8226/7B) was highly sensitive to Apo2L/TRAIL-induced apoptosis. Moreover, RPMI 8226 cells overexpressing Mcl-1 (8226/Mcl-1) or Bcl-x(L) (8226/Bcl-x(L)) also showed enhanced resistance to bortezomib, but co-treatment with Apo2L/TRAIL reverted this resistance. These results indicate that Apo2L/TRAIL can cooperate with bortezomib to induce apoptosis in myeloma cells and can be an useful adjunct for MM therapy.
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Affiliation(s)
- Patricia Balsas
- Departamento de Bioquimica, Biologia Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain
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Sugamura K, Gibbs JF, Belicha-Villanueva A, Andrews C, Repasky EA, Hylander BL. Synergism of CPT-11 and Apo2L/TRAIL against two differentially sensitive human colon tumor xenografts. Oncology 2008; 74:188-97. [PMID: 18714167 DOI: 10.1159/000151366] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2006] [Accepted: 03/26/2008] [Indexed: 01/05/2023]
Abstract
OBJECTIVE The ability to sustain and grow portions of human tumors as xenografts in SCID mice provides a valuable preclinical opportunity to test the response of human tumors to treatments, both individually and in combination. Using this model, our laboratory has previously demonstrated that the growth of several human adenocarcinomas can be inhibited by Apo2L/TRAIL. Apo2L/TRAIL triggers apoptosis in many types of tumor cells, and when combined with various chemotherapeutic agents results in enhanced inhibition of tumor growth in many xenograft models. METHODS To gain further insight into the antitumor potential of Apo2L/TRAIL in combination with chemotherapy, we compared the responses of 2 human colon adenocarcinomas, both of which were sensitive to CPT-11 while one was sensitive and the other comparatively resistant to Apo2L/TRAIL. RESULTS In both cases, a greater degree of growth inhibition was achieved when these agents were used in combination. Western blot analysis demonstrated that in the Apo2L/TRAIL-sensitive tumor total cellular expression of Apo2L/TRAIL death receptors (DR4 and DR5) as well as protein expression of the pro-apoptotic molecule BAX were higher and the anti-apoptotic molecule Bcl-2 was lower in comparison to the Apo2L/TRAIL-resistant tumor. CONCLUSION These results indicate that both Apo2L/TRAIL-sensitive and -resistant colon tumors will respond to a combination of CPT-11 and Apo2L/TRAIL and predict that this will be useful in the treatment of human colon cancers in a clinical setting.
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Affiliation(s)
- Kenji Sugamura
- First Department of Surgery, Tottori University School of Medicine, Yonago, Japan
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Ashkenazi A, Holland P, Eckhardt SG. 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 2008; 26:3621-30. [PMID: 18640940 DOI: 10.1200/jco.2007.15.7198] [Citation(s) in RCA: 339] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cancer is a leading cause of premature human death and commands considerable research attention. Apoptosis (type 1 programmed cell death) is critical in maintaining tissue homeostasis in metazoan organisms, and its dysregulation underpins the initiation and progression of cancer. Conventional chemotherapy and radiotherapy can induce apoptosis as a secondary consequence of inflicting cell damage. However, more direct and selective strategies to manipulate the apoptotic process in cancer cells are emerging as potential therapeutic tools. Genetic and biochemical understanding of the cellular signaling mechanisms that control apoptosis has increased substantially during the last decade. These advances provide a strong scientific framework for developing several types of targeted proapoptotic anticancer therapies. One promising class of agents is the proapoptotic receptor agonists. Of these, recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL)-an optimized soluble form of an endogenous apoptosis-inducing ligand-is unique in that it activates two related proapoptotic receptors, DR4 and DR5. Preclinical data indicate that rhApo2L/TRAIL can induce apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. In vitro, and in various in vivo tumor xenograft models, rhApo2L/TRAIL exhibits single-agent antitumor activity and/or cooperation with certain conventional and targeted therapies. Preclinical safety studies in nonhuman primates show rhApo2L/TRAIL to be well tolerated. Moreover, early clinical trial data suggest that rhApo2L/TRAIL is generally safe and provide preliminary evidence for potential antitumor activity. Clinical studies are ongoing to assess the safety and efficacy of this novel agent in combination with established anticancer therapies.
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Affiliation(s)
- Avi Ashkenazi
- Department of Molecular Oncology, Genentech Inc, South San Francisco, CA 94080, USA.
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Chamoux E, Houde N, L'Eriger K, Roux S. Osteoprotegerin decreases human osteoclast apoptosis by inhibiting the TRAIL pathway. J Cell Physiol 2008; 216:536-42. [PMID: 18338379 DOI: 10.1002/jcp.21430] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Osteoprotegerin (OPG) is a secreted decoy receptor that recognizes RANKL, and blocks the interaction between RANK and RANKL, leading to the inhibition of osteoclast differentiation and activation. As OPG is a major inhibitor of bone resorption, we wondered whether OPG could modulate osteoclast survival/apoptosis. Osteoclast apoptosis was evaluated by adding various doses of OPG to human osteoclast cultures obtained from cord blood monocytes. Surprisingly, apoptosis decreased after adding the OPG. We hypothesized that OPG may block its second ligand, TRAIL, which is involved in osteoclast apoptosis. We showed that osteoclasts expressed TRAIL, and that TRAIL levels in the culture medium dose-dependently decreased in presence of OPG, as did the level of activated caspase-8 in osteoclasts. In addition, the expression of TRAIL by osteoclasts was not affected in the presence of OPG. Our findings suggest that OPG inhibits osteoclast apoptosis, at least in part, by binding and thus inhibiting endogenously produced TRAIL in human osteoclast cultures. TRAIL could be an autocrine factor for the regulation of osteoclast survival/apoptosis.
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Affiliation(s)
- Estelle Chamoux
- Division of Rheumatology, Department of Medicine, Sherbrooke University, Sherbrooke, Quebec, Canada
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36
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Cao L, Du P, Jiang SH, Jin GH, Huang QL, Hua ZC. Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature. Mol Cancer Ther 2008; 7:851-61. [DOI: 10.1158/1535-7163.mct-07-0533] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008; 29:155-92. [PMID: 18057140 PMCID: PMC2528846 DOI: 10.1210/er.2007-0014] [Citation(s) in RCA: 566] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Accepted: 11/15/2007] [Indexed: 12/13/2022]
Abstract
Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.
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Affiliation(s)
- Ann E Kearns
- Endocrine Research Unit, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
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Stieglmaier J, Bremer E, Kellner C, Liebig TM, ten Cate B, Peipp M, Schulze-Koops H, Pfeiffer M, Bühring HJ, Greil J, Oduncu F, Emmerich B, Fey GH, Helfrich W. Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAIL fusion protein. Cancer Immunol Immunother 2008; 57:233-46. [PMID: 17665197 PMCID: PMC11030665 DOI: 10.1007/s00262-007-0370-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2007] [Accepted: 07/04/2007] [Indexed: 12/24/2022]
Abstract
Although the treatment outcome of lymphoid malignancies has improved in recent years by the introduction of transplantation and antibody-based therapeutics, relapse remains a major problem. Therefore, new therapeutic options are urgently needed. One promising approach is the selective activation of apoptosis in tumor cells by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This study investigated the pro-apoptotic potential of a novel TRAIL fusion protein designated scFvCD19:sTRAIL, consisting of a CD19-specific single-chain Fv antibody fragment (scFv) fused to the soluble extracellular domain of TRAIL (sTRAIL). Potent apoptosis was induced by scFvCD19:sTRAIL in several CD19-positive tumor cell lines, whereas normal blood cells remained unaffected. In mixed culture experiments, selective binding of scFvCD19:sTRAIL to CD19-positive cells resulted in strong induction of apoptosis in CD19-negative bystander tumor cells. Simultaneous treatment of CD19-positive cell lines with scFvCD19:sTRAIL and valproic acid (VPA) or Cyclosporin A induced strongly synergistic apoptosis. Treatment of patient-derived acute B-lymphoblastic leukemia (B-ALL) and chronic B-lymphocytic leukemia (B-CLL) cells resulted in strong tumoricidal activity that was further enhanced by combination with VPA. In addition, scFvCD19:sTRAIL prevented engraftment of human Nalm-6 cells in xenotransplanted NOD/Scid mice. The pre-clinical data presented here warrant further investigation of scFvCD19:sTRAIL as a potential new therapeutic agent for CD19-positive B-lineage malignancies.
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Affiliation(s)
- Julia Stieglmaier
- Chair of Genetics, University of Erlangen-Nuremberg, BTE-Building, Erwin-Rommel-Straße 3, 91058 Erlangen, Germany
| | - Edwin Bremer
- Groningen University Institute for Drug Exploration, Department of Pathology and Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, University Medical Center, Groningen, The Netherlands
| | - Christian Kellner
- Chair of Genetics, University of Erlangen-Nuremberg, BTE-Building, Erwin-Rommel-Straße 3, 91058 Erlangen, Germany
| | - Tanja M. Liebig
- Department of Molecular Tumorbiology and Tumorimmunology, University Medical Center, Cologne, Germany
| | - Bram ten Cate
- Groningen University Institute for Drug Exploration, Department of Pathology and Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, University Medical Center, Groningen, The Netherlands
| | - Matthias Peipp
- Section of Stem Cell Transplantation and Immunotherapy, University Medical Center University of Schleswig-Holstein, Kiel, Germany
| | - Hendrik Schulze-Koops
- Clinical Research Group III, Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Matthias Pfeiffer
- Department of Pediatric Oncology, University Children’s Hospital, Tuebingen, Germany
| | - Hans-Jörg Bühring
- Department of Internal Medicine II, University Hospital, Tuebingen, Germany
| | - Johann Greil
- Department of Pediatrics III, University Children’s Hospital, Heidelberg, Germany
| | - Fuat Oduncu
- Medizinische Klinik-Innenstadt, Klinikum der Universität München, München, Germany
| | - Bertold Emmerich
- Medizinische Klinik-Innenstadt, Klinikum der Universität München, München, Germany
| | - Georg H. Fey
- Chair of Genetics, University of Erlangen-Nuremberg, BTE-Building, Erwin-Rommel-Straße 3, 91058 Erlangen, Germany
| | - Wijnand Helfrich
- Groningen University Institute for Drug Exploration, Department of Pathology and Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, University Medical Center, Groningen, The Netherlands
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Locklin RM, Federici E, Espina B, Hulley PA, Russell RGG, Edwards CM. Selective targeting of death receptor 5 circumvents resistance of MG-63 osteosarcoma cells to TRAIL-induced apoptosis. Mol Cancer Ther 2007; 6:3219-28. [PMID: 18065493 PMCID: PMC2816033 DOI: 10.1158/1535-7163.mct-07-0275] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a tumor necrosis factor superfamily member, targets death receptors and selectively kills malignant cells while leaving normal cells unaffected. However, unlike most cancers, many osteosarcomas are resistant to TRAIL. To investigate this resistance, we characterized the response of MG-63 osteosarcoma cells and hPOB-tert osteoblast-like cells to TRAIL and agonist antibodies to death receptor 4 (DR4) and death receptor 5 (DR5). We found that MG-63 osteosarcoma cells and hPOB-tert osteoblast-like cells show no or very little response to TRAIL or a DR4 agonist, but MG-63 cells undergo apoptosis in response to a DR5 agonist. Analysis of TRAIL receptor expression showed that normal osteoblastic and osteosarcoma cells express a variety of TRAIL receptors but this does not correlate to TRAIL responsiveness. Production of the soluble decoy receptor osteoprotegerin also could not explain TRAIL resistance. We show that TRAIL activates the canonical caspase-dependent pathway, whereas treatment with cycloheximide increases the sensitivity of MG-63 cells to TRAIL and anti-DR5 and can also sensitize hPOB-tert cells to both agents. Proapoptotic and antiapoptotic protein expression does not significantly differ between MG-63 and hPOB-tert cells or change following treatment with TRAIL or anti-DR5. However, sequencing the death domain of DR4 in several osteoblast-like cells showed that MG-63 osteosarcoma cells are heterozygous for a dominant-negative mutation, which can confer TRAIL resistance. These results suggest that although the dominant-negative form of the receptor may block TRAIL-induced death, an agonist antibody to the active death receptor can override cellular defenses and thus provide a tailored approach to treat resistant osteosarcomas.
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Affiliation(s)
- Rachel M Locklin
- Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedic Surgery, University of Oxford, Oxford OX3 7LD, United Kingdom.
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Cheriyath V, Glaser KB, Waring JF, Baz R, Hussein MA, Borden EC. G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells. J Clin Invest 2007; 117:3107-17. [PMID: 17823654 PMCID: PMC1964509 DOI: 10.1172/jci31122] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2006] [Accepted: 06/26/2007] [Indexed: 12/20/2022] Open
Abstract
The effectiveness of IFN-alpha2b for human multiple myeloma has been variable. TRAIL has been proposed to mediate IFN-alpha2b apoptosis in myeloma. In this study we assessed the effects of IFN-alpha2b signaling on the apoptotic activity of TRAIL and human myeloma cell survival. While TRAIL was one of the most potently induced proapoptotic genes in myeloma cells following IFN-alpha2b treatment, less than 20% of myeloma cells underwent apoptosis. Thus, we hypothesized that an IFN-stimulated gene (ISG) with prosurvival activity might suppress TRAIL-mediated apoptosis. Consistent with this, IFN-alpha2b stabilized mitochondria and inhibited caspase-3 activation, which antagonized TRAIL-mediated apoptosis and cytotoxicity after 24 hours of cotreatment in cell lines and in fresh myeloma cells, an effect not evident after 72 hours. Induced expression of G1P3, an ISG with largely unknown function, was correlated with the antiapoptotic activity of IFN-alpha2b. Ectopically expressed G1P3 localized to mitochondria and antagonized TRAIL-mediated mitochondrial potential loss, cytochrome c release, and apoptosis, suggesting specificity of G1P3 for the intrinsic apoptosis pathway. Furthermore, RNAi-mediated downregulation of G1P3 restored IFN-alpha2b-induced apoptosis. Our data identify the direct role of a mitochondria-localized prosurvival ISG in antagonizing the effect of TRAIL. Curtailing G1P3-mediated antiapoptotic signals could improve therapies for myeloma or other malignancies.
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Affiliation(s)
- Venugopalan Cheriyath
- Center for Hematology and Oncology Molecular Therapeutics and
Multiple Myeloma Research Program, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
Cancer Research, Abbott Laboratories, Abbott Park, Illinois, USA
| | - Keith B. Glaser
- Center for Hematology and Oncology Molecular Therapeutics and
Multiple Myeloma Research Program, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
Cancer Research, Abbott Laboratories, Abbott Park, Illinois, USA
| | - Jeffrey F. Waring
- Center for Hematology and Oncology Molecular Therapeutics and
Multiple Myeloma Research Program, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
Cancer Research, Abbott Laboratories, Abbott Park, Illinois, USA
| | - Rachid Baz
- Center for Hematology and Oncology Molecular Therapeutics and
Multiple Myeloma Research Program, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
Cancer Research, Abbott Laboratories, Abbott Park, Illinois, USA
| | - Mohamad A. Hussein
- Center for Hematology and Oncology Molecular Therapeutics and
Multiple Myeloma Research Program, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
Cancer Research, Abbott Laboratories, Abbott Park, Illinois, USA
| | - Ernest C. Borden
- Center for Hematology and Oncology Molecular Therapeutics and
Multiple Myeloma Research Program, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
Cancer Research, Abbott Laboratories, Abbott Park, Illinois, USA
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Mérino D, Lalaoui N, Morizot A, Solary E, Micheau O. TRAIL in cancer therapy: present and future challenges. Expert Opin Ther Targets 2007; 11:1299-314. [PMID: 17907960 PMCID: PMC2976473 DOI: 10.1517/14728222.11.10.1299] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Since its identification in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. In contrast to other members of the TNF superfamily, TRAIL administration in vivo is safe. The relative absence of toxic side effects of this naturally occurring cytokine, in addition to its antitumoural properties, has led to its preclinical evaluation. However, despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity or efficiency. An appropriate understanding of its physiological relevance, and of the mechanisms controlling cancer cells escape from TRAIL-induced cell death, will be required to optimally use the cytokine in clinics. The present review focuses on recent advances in the understanding of TRAIL signal transduction and discusses the existing and future challenges of TRAIL-based cancer therapy development.
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42
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Gómez-Benito M, Martinez-Lorenzo MJ, Anel A, Marzo I, Naval J. Membrane expression of DR4, DR5 and caspase-8 levels, but not Mcl-1, determine sensitivity of human myeloma cells to Apo2L/TRAIL. Exp Cell Res 2007; 313:2378-88. [PMID: 17462628 DOI: 10.1016/j.yexcr.2007.03.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2006] [Revised: 03/15/2007] [Accepted: 03/18/2007] [Indexed: 11/16/2022]
Abstract
The improved recombinant form of the death ligand Apo2L/TRAIL (Apo2L/TRAIL.0) is not cytotoxic for normal human cells and is a good candidate for the therapy of multiple myeloma (MM), a B-cell neoplasia that remains incurable. We have analyzed the molecular determinants of myeloma sensitivity to Apo2L/TRAIL.0 in a number of MM cell lines, the mechanisms of resistance and a possible way of overcoming it. Expression of one death receptor for Apo2L/TRAIL (DR4 or DR5) is sufficient to transduce death signals, though DR5 was more efficient when both receptors were present. Membrane expression of decoy receptors (DcR1, DcR2) and intracellular levels of c-FLIP(L), XIAP and Mcl-1 were not predictive of resistance to Apo2L/TRAIL. Inhibition of Mcl-1 degradation did not prevent Apo2L/TRAIL-induced apoptosis. In IM-9 cells, resistance was associated to a reduced caspase-8 expression. U266 cells, though expressing significant levels of DR4 and caspase-8, were nevertheless resistant to Apo2L/TRAIL. This resistance could be overcome by co-treatment with valproic acid (VPA), a histone deacetylase inhibitor. VPA caused the redistribution of DR4 to plasma membrane lipid rafts and restored DR4 signaling. Overexpression of Mcl-1 in U266 cells did not prevent Apo2L/TRAIL cytotoxicity in VPA-sensitized cells. These results, taken together, support the possible use of Apo2L/TRAIL.0 in the treatment of MM.
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Affiliation(s)
- Maria Gómez-Benito
- Departamento de Bioquímica y Biologia Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain
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Locklin RM, Croucher PI, Russell RGG, Edwards CM. Agonists of TRAIL death receptors induce myeloma cell apoptosis that is not prevented by cells of the bone marrow microenvironment. Leukemia 2007; 21:805-12. [PMID: 17315027 DOI: 10.1038/sj.leu.2404518] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The growth and survival of myeloma cells is critically regulated by cells of the bone marrow microenvironment, including osteoblasts. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of myeloma cell apoptosis, however, this antimyeloma activity is inhibited by osteoprotegerin (OPG) released from osteoblasts. Therefore, we hypothesized that specific agonists of TRAIL death receptors would not be inhibited by OPG released from osteoblasts and thus may represent a novel therapeutic approach in multiple myeloma. In the present study, TRAIL-induced apoptosis was demonstrated to be mediated through both DR4 and DR5. Specific agonist antibodies to DR4 or DR5 dose-dependently induced myeloma cell apoptosis, which was not prevented by OPG or by medium conditioned by osteoblasts. Co-culture of myeloma cells with osteoblasts protected against TRAIL-induced apoptosis of myeloma cells, and this protective effect was due to OPG. In contrast, the co-culture of myeloma cells with osteoblasts had no protective effect on apoptosis induced by specific agonists of DR4 or DR5. TRAIL has been proposed as a potential antitumour therapy, but within the bone marrow microenvironment OPG may interfere with the action of TRAIL. Specific agonists of TRAIL death receptors would not be subject to this inhibition and thus may provide an alternative specific antimyeloma therapy.
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Affiliation(s)
- R M Locklin
- Nuffield Department of Orthopaedic Surgery, Institute of Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK
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45
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Tinhofer I, Biedermann R, Krismer M, Crazzolara R, Greil R. A role of TRAIL in killing osteoblasts by myeloma cells. FASEB J 2006; 20:759-61. [PMID: 16436464 DOI: 10.1096/fj.05-4329fje] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In multiple myeloma (MM), neoplastic plasma cells accumulate in the bone marrow where their survival, proliferation, and apoptosis are controlled at multiple levels by interaction with the bone marrow microenvironment. Myeloma cells actively control these interactions by activating stromal and endothelial cells for production of survival factors, such as interleukin-6, and suppressing other cell types such as erythroblasts, normal B cell progenitors, and T-cells. In the present study, we identified primary osteoblasts as additional potential targets for myeloma cell-mediated suppression which was partly dependent on the death receptor ligand TRAIL. Besides killing of osteoblasts, myeloma cell lines sensitized osteoblasts to cell death mediated by recombinant TRAIL, whereas primary osteoblasts protected myeloma cells from TRAIL-mediated apoptosis that was mediated by osteoprotegerin (OPG). Besides increase of osteoclastogenesis and osteoclast activity, suppression of bone-forming cells by myeloma cells might contribute to bone loss in MM patients. In addition, clinical development of recombinant TRAIL as anti-myeloma therapy should include evaluation of potential side effects on viability of normal bone cells.
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Affiliation(s)
- Inge Tinhofer
- Laboratory of Immunological and Molecular Cancer Research, 3rd Medical Department of the Salzburg General Hospital and Private Paracelsus Medical University, Salzburg, Austria.
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Abstract
Multiple myeloma, the second most common haematopoietic cancer, represents a collection of plasma-cell neoplasms that invariably become fatal when self-renewing myeloma cells begin unrestrained proliferation. Myeloma cells are arrested as intermediates in plasma-cell differentiation as a consequence of transformation. Unlike normal plasma cells, myeloma cells retain the self-renewing potential. Although impaired apoptosis accounts for the accumulation of myeloma cells in the bone marrow during the plateau phase of the disease, cell-cycle deregulation underlies unrestrained proliferation of self-renewing myeloma cells in aggressive myelomas and during relapse. The mechanism that governs deregulated cell-cycle re-entry and progression in multiple myeloma is unknown, and the relationship between myeloma cells and their normal counterparts is undefined. Plasma-cell differentiation is a complex multi-step process. This chapter will address recent advances in the mechanism of normal plasma-cell differentiation and our current understanding of the relationship between plasma-cell differentiation and myeloma pathogenesis.
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Affiliation(s)
- S Chen-Kiang
- Department of Pathology and Laboratory Medicine and Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
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47
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Affiliation(s)
- Georgios V Georgakis
- Department of Lymphoma/Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
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48
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Roux S, Lambert-Comeau P, Saint-Pierre C, Lépine M, Sawan B, Parent JL. Death receptors, Fas and TRAIL receptors, are involved in human osteoclast apoptosis. Biochem Biophys Res Commun 2005; 333:42-50. [PMID: 15936719 DOI: 10.1016/j.bbrc.2005.05.092] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2005] [Accepted: 05/14/2005] [Indexed: 11/26/2022]
Abstract
Survival and apoptosis are crucial aspects of the osteoclast life cycle. Although osteoclast survival has been extensively studied, little is known about the mechanisms involved in human osteoclast apoptosis. In the present study, cord blood monocytes (CBMs) were used as the source of human osteoclast precursors. When cultured in the presence of M-CSF and RANKL, CBMs formed multinucleated cells that expressed RANK and calcitonin receptor, and were able to resorb bone. These cells expressed TRAIL receptors (R1-R4). Surprisingly, although TRAIL-receptor expression was not detectable in osteoclasts from normal bone, osteoclasts from myeloma specimens did express TRAIL receptors to a variable extent. Significantly, we have shown for the first time that this pathway is indeed functional in human osteoclasts, and that apoptosis occurred and was significantly greater in the presence of TRAIL. In addition, we have shown that a Fas-activating antibody is also able to induce osteoclast apoptosis, as did TGFbeta, whereas the survival factor M-CSF decreased apoptosis. Overall, these findings suggest that death receptors, TRAIL receptors and Fas, could be involved in osteoclast apoptosis in humans.
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Affiliation(s)
- Sophie Roux
- Department of Medicine, Division of Rheumatology, Sherbrooke University, Quebec, Canada.
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49
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Bremer E, Samplonius DF, Peipp M, van Genne L, Kroesen BJ, Fey GH, Gramatzki M, de Leij LFMH, Helfrich W. Target Cell–Restricted Apoptosis Induction of Acute Leukemic T Cells by a Recombinant Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Fusion Protein with Specificity for Human CD7. Cancer Res 2005; 65:3380-8. [PMID: 15833872 DOI: 10.1158/0008-5472.can-04-2756] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Current treatment of human T-cell leukemia and lymphoma is predominantly limited to conventional cytotoxic therapy and is associated with limited therapeutic response and significant morbidity. Therefore, more potent and leukemia-specific therapies with favorable toxicity profiles are urgently needed. Here, we report on the construction of a novel therapeutic fusion protein, scFvCD7:sTRAIL, designed to induce target antigen-restricted apoptosis in human T-cell tumors. ScFvCD7:sTRAIL consists of the death-inducing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genetically linked to an scFv antibody fragment specific for the T-cell surface antigen CD7. Treatment with scFvCD7:sTRAIL induced potent CD7-restricted apoptosis in a series of malignant T-cell lines, whereas normal resting leukocytes, activated T cells, and vascular endothelial cells (human umbilical vein endothelial cells) showed no detectable apoptosis. The apoptosis-inducing activity of scFvCD7:sTRAIL was stronger than that of the immunotoxin scFvCD7:ETA. In mixed culture experiments with CD7-positive and CD7-negative tumor cells, scFvCD7:sTRAIL induced very potent bystander apoptosis of CD7-negative tumor cells. In vitro treatment of blood cells freshly derived from T-acute lymphoblastic leukemia patients resulted in marked apoptosis of the malignant T cells that was strongly augmented by vincristin. In conclusion, scFvCD7:sTRAIL is a novel recombinant protein causing restricted apoptosis in human leukemic T cells with low toxicity for normal human blood and endothelial cells.
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Affiliation(s)
- Edwin Bremer
- Laboratory for Tumor Immunology, Department of Pathology and Laboratory Medicine, Section Medical Biology, University Hospital Groningen, Groningen University Institute for Drug Exploration, 9713 GZ Groningen, the Netherlands
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Abstract
Identification of tumour necrosis factor apoptosis inducing ligand (TRAIL), a TNF family ligand, sparked a torrent of research, following an initial observation that it could kill tumour cells, but spare normal cells. Almost a decade after its discovery, and with five known receptors, the true physiological role of TRAIL is still debated and its anti-tumorigenic properties limited by potential toxicity. This review takes a comprehensive look at the story of this enigmatic ligand, addressing its remaining potential as a therapeutic and providing an overview of the TRAIL receptors themselves.
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Affiliation(s)
- Fiona C Kimberley
- Department of Medicine, Hammersmith Hospital, Imperial College, Du Cane Road, London, UK
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