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Kaczmarek K, Więckiewicz J, Que I, Gałuszka-Bulaga A, Chan A, Siedlar M, Baran J. Human Soluble TRAIL Secreted by Modified Lactococcus lactis Bacteria Promotes Tumor Growth in the Orthotopic Mouse Model of Colorectal Cancer. Arch Immunol Ther Exp (Warsz) 2024; 72:aite-2024-0002. [PMID: 38299562 DOI: 10.2478/aite-2024-0002] [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: 07/05/2023] [Accepted: 11/30/2023] [Indexed: 02/02/2024]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of sensitive cancer cells, including colorectal cancer (CRC). Due to its short biological half-life after intravenous administration and related clinical ineffectiveness, novel formulations of TRAIL need to be developed. Here we propose Lactococcus lactis bacteria as a vehicle for local delivery of human soluble TRAIL (hsTRAIL) in CRC. The use of common probiotics targeting guts as carriers for TRAIL could ensure its sustained release at the tumor site and extend the duration of its activity. We have already engineered hsTRAIL-secreting L.lactis bacteria and showed their effectiveness in elimination of human CRC cells in vitro and in vivo in a mouse subcutaneous model. Here, L.lactis(hsTRAIL+) were administered by gastric gavage to SCID mice with orthotopically developed HCT116 tumor in cecum, in monotherapy or in combination with metformin (MetF), already shown to enhance the hsTRAIL anti-tumor activity in subcutaneous CRC model. Oral administration of L.lactis(hsTRAIL+) resulted in significant progression of HCT116 tumors and shortening of the colon crypts. Secretion of hsTRAIL in the colon was accompanied by infiltration of the primary tumor with M2-macrophages, while MetF promoted transient colonization of the gut by L.lactis. Our study indicates that L.lactis bacteria after oral administration enable delivery of biologically active hsTRAIL to colon, however its potential therapeutic effect in CRC treatment is abolished by its pro-tumorigenic signalling, leading to the recruitment of M2-macrophages and tumor growth promotion.
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Affiliation(s)
- Katarzyna Kaczmarek
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Jerzy Więckiewicz
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Ivo Que
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
- Currently: Department of Radiology and Nuclear Medicine, Department of Molecular Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Adrianna Gałuszka-Bulaga
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Alan Chan
- Percuros B.V., Zernikedreef 8, 2333 CL Leiden, The Netherlands
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Jarek Baran
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
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Circulating Protein Biomarkers for Prognostic Use in Patients with Advanced Pancreatic Ductal Adenocarcinoma Undergoing Chemotherapy. Cancers (Basel) 2022; 14:cancers14133250. [PMID: 35805022 PMCID: PMC9264968 DOI: 10.3390/cancers14133250] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/25/2022] [Accepted: 06/28/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a dismal prognosis. We aimed to find a prognostic protein signature for overall survival (OS) in patients with advanced PDAC, and to explore whether early changes in circulating-protein levels could predict survival. We investigated 92 proteins using the Olink Immuno-Oncology panel in serum samples from 363 patients with advanced PDAC. Protein panels for several survival cut-offs were developed independently by two bioinformaticians using LASSO and Ridge regression models. Two panels of proteins discriminated patients with OS < 90 days from those with OS > 2 years. Index I (CSF-1, IL-6, PDCD1, TNFRSF12A, TRAIL, TWEAK, and CA19-9) had AUCs of 0.99 (95% CI: 0.98−1) (discovery cohort) and 0.89 (0.74−1) (replication cohort). For Index II (CXCL13, IL-6, PDCD1, and TNFRSF12A), the corresponding AUCs were 0.97 (0.93−1) and 0.82 (0.68−0.96). Four proteins (ANGPT2, IL-6, IL-10, and TNFRSF12A) were associated with survival across all treatment groups. Longitudinal samples revealed several changes, including four proteins that were also part of the prognostic signatures (CSF-1, CXCL13, IL-6, TNFRSF12A). This study identified two circulating-protein indices with the potential to identify patients with advanced PDAC with very short OS and with long OS.
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Antibody therapy in pancreatic cancer: mAb-ye we're onto something? Biochim Biophys Acta Rev Cancer 2021; 1876:188557. [PMID: 33945846 DOI: 10.1016/j.bbcan.2021.188557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/23/2021] [Accepted: 04/25/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer remains an extremely deadly disease, with little improvement seen in treatment or outcomes over the last 40 years. Targeted monoclonal antibody therapy is one area that has been explored in attempts to tackle this disease. This review examines antibodies that have undergone clinical evaluation in pancreatic cancer. These antibodies target a wide variety of molecules, including tumour cell surface, stromal, immune and embryonic pathway targets. We discuss the therapeutic utility of these therapies both as monotherapeutics and in combination with other treatments such as chemotherapy. While antibody therapy for pancreatic cancer has yet to yield significant success, lessons learned from research thus far highlights future directions that may help overcome observed hurdles to yield clinically efficacious results.
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Kaur J, Singh P, Enzler T, Sahai V. Emerging antibody therapies for pancreatic adenocarcinoma: a review of recent phase 2 trials. Expert Opin Emerg Drugs 2021; 26:103-129. [PMID: 33734833 DOI: 10.1080/14728214.2021.1905795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Pancreatic adenocarcinoma is now the third-leading cause of cancer-related deaths in the US which can be attributed to rising incidence, diagnosis at advanced stages and early development of metastasis. Systemic therapy remains palliative with early development of resistance possibly related to the constitutive activation of 'undruggable' KRAS, immunosuppressive microenvironment, and intense desmoplasia. The advancements in molecular biology has led to the development and investigation of targeted and immune therapeutics.Areas covered: This study provides a comprehensive review of the literature to further the understanding of molecular targets with their respective antibody-based therapies in clinical development in pancreatic cancer. PubMed was systematically searched for English-language articles discussing antibody-based therapies under phase 2 clinical trial investigation in pancreatic adenocarcinoma.Expert opinion: PDAC remains highly resistant to chemotherapy with no significant improvement in survival for patients with advanced or metastatic cancer. Unfortunately, the majority of the antibody-based targeted and immune therapeutics have failed to meet their primary efficacy endpoints in early phase trials. However, there are a few promising antibody-based drugs with intriguing preliminary data that merit further investigation, while many more continue to be developed and investigated preclinically, and in early phase trials.
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Affiliation(s)
- Jasmeet Kaur
- Department of Internal Medicine, Saint Joseph Mercy Oakland Hospital, Pontiac, MI, USA
| | - Paramveer Singh
- Division of Hematology and Oncology, Department of Internal Medicine, Wayne State University, Detroit, MI, USA
| | - Thomas Enzler
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Vaibhav Sahai
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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Apoptosis-Inducing TNF Superfamily Ligands for Cancer Therapy. Cancers (Basel) 2021; 13:cancers13071543. [PMID: 33801589 PMCID: PMC8036978 DOI: 10.3390/cancers13071543] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/21/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is a complex disease with apoptosis evasion as one of its hallmarks; therefore, apoptosis induction in transformed cells seems a promising approach as a cancer treatment. TNF apoptosis-inducing ligands, which are naturally present in the body and possess tumoricidal activity, are attractive candidates. The most studied proteins are TNF-α, FasL, and TNF-related apoptosis-inducing ligand (TRAIL). Over the years, different recombinant TNF family-derived apoptosis-inducing ligands and agonists have been designed. Their stability, specificity, and half-life have been improved because most of the TNF ligands have the disadvantages of having a short half-life and affinity to more than one receptor. Here, we review the outlook on apoptosis-inducing ligands as cancer treatments in diverse preclinical and clinical stages and summarize strategies of overcoming their natural limitations to improve their effectiveness.
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Zheng H, Zhang Y, Zhan Y, Liu S, Lu J, Wen Q, Fan S. Expression of DR5 and c‑FLIP proteins as novel prognostic biomarkers for non‑small cell lung cancer patients treated with surgical resection and chemotherapy. Oncol Rep 2019; 42:2363-2370. [PMID: 31638235 PMCID: PMC6859453 DOI: 10.3892/or.2019.7355] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 09/12/2019] [Indexed: 12/16/2022] Open
Abstract
TRAIL-R2 (DR5), one of the death receptors, can activate the extrinsic apoptosis pathway, while cellular FLICE-inhibitory protein (c-FLIP) can inhibit this pathway. Both of them play important roles in the occurrence and development of most tumors. To date, there is no relevant report concerning the relationship between expression of DR5 and c-FLIP protein and clinicopathological/prognostic implications in patients with non-small cell lung cancer (NSCLC) treated with surgical resection and chemotherapy. Thus, the aim of the present study was to investigate the potential prognostic significance of DR5 and c-FLIP in NSCLC patients and their predictive roles in the chemotherapeutic response. In the present study, DR5 and c-FLIP were detected by immunohistochemistry (IHC) in tissue microarrays of NSCLC. The results showed that the expression levels of DR5 and c-FLIP were significantly higher in lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC) tissues compared with levels noted in the non-cancerous control lung tissues (all P<0.05). In addition, DR5 expression was significantly increased in lung ADC (P<0.001), whereas, c-FLIP was higher in lung SCC (P<0.001) and smoker patients with clinical stage III (P=0.019, P=0.016, respectively). In addition, NSCLC patients with overexpression of DR5 and loss of c-FLIP expression exhibited a higher overall survival (OS) rate as determined by Kaplan-Meier analysis (P=0.029, P=0.038, respectively). Multivariate analysis confirmed that high expression of DR5 and loss of c-FLIP expression were independent favorable prognostic factors for NSCLC patients (P=0.016, P=0.035, respectively). In conclusion, overexpression of DR5 and loss of c-FLIP expression may serve as novel favorable prognostic biomarkers for NSCLC patients treated with chemotherapy after radical resection and used as predictors for tumor response to chemotherapy drugs.
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Affiliation(s)
- Hongmei Zheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yuting Zhang
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yuting Zhan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Sile Liu
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Junmi Lu
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Qiuyuan Wen
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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Lukosiute-Urboniene A, Jasukaitiene A, Silkuniene G, Barauskas V, Gulbinas A, Dambrauskas Z. Human antigen R mediated post-transcriptional regulation of inhibitors of apoptosis proteins in pancreatic cancer. World J Gastroenterol 2019; 25:205-219. [PMID: 30670910 PMCID: PMC6337016 DOI: 10.3748/wjg.v25.i2.205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/06/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the association of human antigen R (HuR) and inhibitors of apoptosis proteins (IAP1, IAP2) and prognosis in pancreatic cancer. METHODS Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreatic ductal adenocarcinoma (PDAC) were compared with normal pancreatic tissue. The correlations among IAP1/IAP2 and HuR as well as their respective correlations with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for survival analysis. Immunoprecipitation assay was performed to demonstrate HuR binding to IAP1, IAP2 mRNA. PANC1 cells were transfected with either anti-HuR siRNA or control siRNA for 72 h and quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot analysis was carried out. RESULTS RT-PCR analysis revealed that HuR, IAP1, IAP2 mRNA expression were accordingly 3.3-fold, 5.5-fold and 8.4 higher in the PDAC when compared to normal pancreas (P < 0.05). Expression of IAP1 was positively strongly correlated with HuR expression (P < 0.05, r = 0.783). Western blot analysis confirmed RT-PCR results. High IAP1 expression, tumor resection status, T stage, lymph-node metastases, tumor differentiation grade, perineural and lymphatic invasion were identified as significant factors for shorter survival in PDAC patients (P < 0.05). Immunohistological analysis showed that HuR was mainly expressed in the ductal cancer cell's nucleus and less so in cytoplasm. RNA immunoprecipitation analysis confirmed IAP1 and IAP2 post-transcriptional regulation by HuR protein. Following siHuR transfection, IAP1 mRNA and protein levels were decreased, however IAP2 expression levels were increased. CONCLUSION HuR mediated overexpression of IAP1 significantly correlates with poor outcomes and early progression of pancreatic cancer. Further studies are needed to assess the underlying mechanisms.
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MESH Headings
- Aged
- Aged, 80 and over
- Baculoviral IAP Repeat-Containing 3 Protein/genetics
- Baculoviral IAP Repeat-Containing 3 Protein/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- ELAV-Like Protein 1/genetics
- ELAV-Like Protein 1/metabolism
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Inhibitor of Apoptosis Proteins/genetics
- Inhibitor of Apoptosis Proteins/metabolism
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Grading
- Pancreas/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Prognosis
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism
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Affiliation(s)
- Ausra Lukosiute-Urboniene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Pediatric Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Aldona Jasukaitiene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Giedre Silkuniene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Vidmantas Barauskas
- Department of Pediatric Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Antanas Gulbinas
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Zilvinas Dambrauskas
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
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Hu J, Wang H, Gu J, Liu X, Zhou X. Trail armed oncolytic poxvirus suppresses lung cancer cell by inducing apoptosis. Acta Biochim Biophys Sin (Shanghai) 2018; 50:1018-1027. [PMID: 30137199 DOI: 10.1093/abbs/gmy096] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Indexed: 12/11/2022] Open
Abstract
Lung cancer has a high morbidity rate worldwide and is often resistant to therapy. Oncolytic virus therapy is a developing trend for cancer treatment. Thus, we constructed an oncolytic poxvirus carrying human trail gene that expresses a membrane-binding tumor necrosis factor and associated apoptosis-inducing ligand (TRAIL, Oncopox-trail). We hypothesized that the expression of trail would increase the efficacy of the oncolytic poxvirus. The effect of the TRAIL protein depends on the death receptors on the surface of different cancer cells. The expression of death receptors in lung cancer cell lines was analyzed by western blot analysis. In vitro, the oncolytic poxvirus carrying the trail gene displayed a better cytotoxicity at the cell level in the lung cancer cell line than that carrying the Oncopox-empty. TRAIL protein mainly induced apoptosis and inhibited necrosis. In vivo, two transplanted tumor models of human A549 lung cancer cells and mouse Lewis lung cancer cells were used to verify the anti-cancer effect of the oncolytic poxvirus carrying the trail gene. TUNEL staining results of the tumor histological sections also verified the anti-cancer effect. Similarly, through systemic administration of Oncopox-trail, the oncolytic poxvirus also exhibited anti-cancer effect.
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Affiliation(s)
- Jinqing Hu
- Laboratory of Cell Biology, Xin-yuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - Huaiyuan Wang
- State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jinfa Gu
- State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xinyuan Liu
- Laboratory of Cell Biology, Xin-yuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
- State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiumei Zhou
- Laboratory of Cell Biology, Xin-yuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
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Han J, Hwang HS, Na K. TRAIL-secreting human mesenchymal stem cells engineered by a non-viral vector and photochemical internalization for pancreatic cancer gene therapy. Biomaterials 2018; 182:259-268. [PMID: 30142525 DOI: 10.1016/j.biomaterials.2018.08.024] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 08/06/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising therapeutic protein to selectively induce cancer cell apoptosis. However, TRAIL exhibits low stability and short half-life due to its denaturation. Thus, delivering the TRAIL gene for stem cell-mediated gene therapy was conducted by using non-viral vectors (a less efficient but safer method). To overcome the limitation of non-viral vectors, photochemical internalization (PCI) was utilized for enhanced transfection efficiency of secreting TRAIL from human mesenchymal stem cells (hMSCs). To explore a more effective approach for cancer treatment, polyplexes were formed by using TRAIL plasmid (pTRAIL) and branched polyethyleneimine (bPEI). PCI is applied to improve polyplex entrapping in hMSCs and enhance the transfection efficiency of TRAIL into hMSCs for secretion in tumors via a homing effect. We demonstrate that PCI-mediated polyplex loading significantly enhanced TRAIL expression in stem cells and that homing ability magnified cancer targeting. The xenograft mouse model shows that polyplex loaded hMSCs (pTRAIL/bPEI@hMSCs) under laser irradiation results in a beneficial therapeutic antitumor effect compared to unloaded polyplexes and pTRAIL/bPEI@hMSCs. Taken together, the delivery of PCI-pTRAIL/bPEI@hMSCs offers exciting potential treatments in pancreatic cancer gene therapy via the enhanced the transfection efficiency of TRAIL by PCI system and the tumor homing properties of hMSCs.
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Affiliation(s)
- Jieun Han
- Center for Photomedicine, Department of Biotechnology, The Catholic University of Korea, 43 Jibongro, Wonmi-gu, Bucheon-si, Gyeonggi do 14662, Republic of Korea
| | - Hee Sook Hwang
- Center for Photomedicine, Department of Biotechnology, The Catholic University of Korea, 43 Jibongro, Wonmi-gu, Bucheon-si, Gyeonggi do 14662, Republic of Korea
| | - Kun Na
- Center for Photomedicine, Department of Biotechnology, The Catholic University of Korea, 43 Jibongro, Wonmi-gu, Bucheon-si, Gyeonggi do 14662, Republic of Korea.
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10
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Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy. Cancers (Basel) 2018; 10:cancers10030077. [PMID: 29562636 PMCID: PMC5876652 DOI: 10.3390/cancers10030077] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/13/2018] [Accepted: 03/14/2018] [Indexed: 01/05/2023] Open
Abstract
Despite recent advances in oncology, diagnosis, and therapy, treatment of pancreatic ductal adenocarcinoma (PDAC) is still exceedingly challenging. PDAC remains the fourth leading cause of cancer-related deaths worldwide. Poor prognosis is due to the aggressive growth behavior with early invasion and distant metastasis, chemoresistance, and a current lack of adequate screening methods for early detection. Consequently, novel therapeutic approaches are urgently needed. Many hopes for cancer treatment have been placed in the death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) since it was reported to induce apoptosis selectively in tumor cells in vitro and in vivo. TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 (TRAIL-R1) also death receptor 4 (DR4) and TRAIL receptor 2 (TRAIL-R2) also death receptor 5 (DR5) thereby inducing the formation of the death-inducing signaling complex (DISC) and activation of the apoptotic cascade. Unlike chemotherapeutics, TRAIL was shown to be able to induce apoptosis in a p53-independent manner, making TRAIL a promising anticancer approach for p53-mutated tumors. These cancer-selective traits of TRAIL led to the development of TRAIL-R agonists, categorized into either recombinant variants of TRAIL or agonistic antibodies against TRAIL-R1 or TRAIL-R2. However, clinical trials making use of these agonists in various tumor entities including pancreatic cancer were disappointing so far. This is thought to be caused by TRAIL resistance of numerous primary tumor cells, an insufficient agonistic activity of the drug candidates tested, and a lack of suitable biomarkers for patient stratification. Nevertheless, recently gained knowledge on the biology of the TRAIL-TRAIL-R system might now provide the chance to overcome intrinsic or acquired resistance against TRAIL and TRAIL-R agonists. In this review, we summarize the status quo of clinical studies involving TRAIL-R agonists for the treatment of pancreatic cancer and critically discuss the suitability of utilizing the TRAIL-TRAIL-R system for successful treatment.
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11
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Yang SZ, Xu F, Zhou T, Zhao X, McDonald JM, Chen Y. The long non-coding RNA HOTAIR enhances pancreatic cancer resistance to TNF-related apoptosis-inducing ligand. J Biol Chem 2017; 292:10390-10397. [PMID: 28476883 PMCID: PMC5481552 DOI: 10.1074/jbc.m117.786830] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 04/21/2017] [Indexed: 08/11/2023] Open
Abstract
Pancreatic cancer is a malignant neoplasm with a high mortality rate. Therapeutic agents that activate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis have shown promising efficacy, but many pancreatic cancers are resistant to TRAIL therapy. Epigenetic regulation plays important roles in tumor pathogenesis and resistance, and a recent study indicated that the long non-coding RNA HOX transcript antisense RNA (HOTAIR) is overexpressed in pancreatic cancer. However, the role of HOTAIR in pancreatic cancer resistance to anticancer agents is unknown. The present study determined the role of HOTAIR in pancreatic cancer TRAIL resistance and investigated the underlying molecular mechanisms. We observed that TRAIL-resistant pancreatic cancer cells had higher levels of HOTAIR expression, whereas TRAIL-sensitive pancreatic cancer cells had lower HOTAIR levels. Overexpressing HOTAIR in TRAIL-sensitive cells attenuated TRAIL-induced apoptosis, and shRNA-mediated HOTAIR knockdown in TRAIL-resistant PANC-1 cells sensitized them to TRAIL-induced apoptosis. These results support a causative effect of HOTAIR on TRAIL sensitivity. Mechanistically, we found that increased HOTAIR expression inhibited the expression of the TRAIL receptor death receptor 5 (DR5), whereas HOTAIR knockdown increased DR5 expression. We further demonstrated that HOTAIR regulates DR5 expression via the epigenetic regulator enhancer of zeste homolog 2 (EZH2) and that EZH2 controls histone H3 lysine 27 trimethylation on the DR5 gene. Taken together, these results demonstrate that high HOTAIR levels increase the resistance of pancreatic cancer cells to TRAIL-induced apoptosis via epigenetic regulation of DR5 expression. Our study therefore supports the notion that targeting HOTAIR function may represent a strategy to overcome TRAIL resistance in pancreatic cancer.
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Affiliation(s)
| | - Fei Xu
- From the Departments of Pathology
| | | | - Xinyang Zhao
- Biochemistry, University of Alabama at Birmingham and
| | - Jay M McDonald
- From the Departments of Pathology
- the Research Department, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35294
| | - Yabing Chen
- From the Departments of Pathology,
- the Research Department, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35294
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12
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Sun L, Chen C, Zhu A, Huang Y, Zhu H, Yi C. TRAIL mutant membrane penetrating peptide alike-MuR6-TR enhances the antitumor effects of TRAIL in pancreatic carcinoma both in vitro and in vivo. Int J Mol Med 2017; 39:1468-1476. [PMID: 28487979 PMCID: PMC5428941 DOI: 10.3892/ijmm.2017.2968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 04/10/2017] [Indexed: 02/05/2023] Open
Abstract
To remedy the drug resistance of natural tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and enhance its antitumor effects, we prepared a type of TRAIL mutant membrane penetrating peptide alike (TMPPA)‑TRAIL mutant R6 (MuR6-TR) by mutating the N‑terminal of the soluble TRAIL gene sequence. The expressed MuR6‑TR protein was purified to treat pancreatic carcinoma cell lines BxPC‑3 and PANC‑1. The inhibitory effects on the proliferation of BxPC‑3 and PANC‑1 cells was assessed with CCK‑8 assay and compared with natural TRAIL. The antitumor effect of MuR6‑TR was assessed on implant tumors derived from PANC‑1 cells in nude mice and compared with gemcitabine. Finally, the soluble MuR6‑TR gene was successfully mutated with 4 amino acids in the N‑terminal of TRAIL and had a molecular size of 513 bp. The mutant MuR6‑TR was connected to pET32a and verified by enzymatic digestion and sequencing. The recombinant MuR6‑TR was transformed and expressed in Escherichia coli. The CCK‑8 assay results indicated that MuR6‑TR inhibited the growth of BxPC‑3 and PANC‑1 cells in a dose‑dependent manner, with IC50 values of 4.63 and 7.84 ng/ml, respectively, which were much lower than that of natural TRAIL. MuR6‑TR demonstrated a higher inhibitory effect on tumor growth (24.2%) than natural TRAIL (14.4%) and an effect similar to that of gemcitabine at an early period. Thus, the mutant MuR6‑TR exhibited a stronger antitumor effect than that of natural TRAIL both in vivo and in vitro and may have potential therapeutic value for pancreatic carcinoma, which requires further validation.
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Affiliation(s)
- Lei Sun
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University
- No. 4 West China Teaching Hospital, Sichuan University
| | - Chen Chen
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University
| | - Aijing Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University
| | - Ying Huang
- Department of Pathophysiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University
| | - Cheng Yi
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University
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Nogueira DR, Yaylim I, Aamir Q, Kahraman OT, Fayyaz S, Kamran-ul-Hassan Naqvi S, Farooqi AA. TRAIL mediated signaling in pancreatic cancer. Asian Pac J Cancer Prev 2017; 15:5977-82. [PMID: 25124560 DOI: 10.7314/apjcp.2014.15.15.5977] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Research over the years has progressively shown substantial broadening of the tumor necrosis factor alpha- related apoptosis-inducing ligand (TRAIL)-mediated signaling landscape. Increasingly it is being realized that pancreatic cancer is a multifaceted and genomically complex disease. Suppression of tumor suppressors, overexpression of oncogenes, epigenetic silencing, and loss of apoptosis are some of the extensively studied underlying mechanisms. Rapidly accumulating in vitro and in vivo evidence has started to shed light on the resistance mechanisms in pancreatic cancer cells. More interestingly a recent research has opened new horizons of miRNA regulation by DR5 in pancreatic cancer cells. It has been shown that DR5 interacts with the core microprocessor components Drosha and DGCR8, thus impairing processing of primary let-7. Xenografting DR5 silenced pancreatic cancer cells in SCID-mice indicated that there was notable suppression of tumor growth. There is a paradigm shift in our current understanding of TRAIL mediated signaling in pancreatic cancer cells that is now adding new layers of concepts into the existing scientific evidence. In this review we have attempted to provide an overview of recent advances in TRAIL mediated signaling in pancreatic cancer as evidenced byfindings of in vitro and in vivo analyses. Furthermore, we discuss nanotechnological advances with emphasis on PEG-TRAIL and four-arm PEG cross-linked hyaluronic acid (HA) hydrogels to improve availability of TRAIL at target sites.
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Affiliation(s)
- Daniele Rubert Nogueira
- Department of Industrial Pharmacy, Health Science Center, Federal University of Santa Maria, Santa Maria-RS, Brazil E-mail :
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Akinleye A, Iragavarapu C, Furqan M, Cang S, Liu D. Novel agents for advanced pancreatic cancer. Oncotarget 2015; 6:39521-37. [PMID: 26369833 PMCID: PMC4741843 DOI: 10.18632/oncotarget.3999] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 05/20/2015] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is relatively insensitive to conventional chemotherapy. Therefore, novel agents targeting dysregulated pathways (MAPK/ERK, EGFR, TGF-β, HEDGEHOG, NOTCH, IGF, PARP, PI3K/AKT, RAS, and Src) are being explored in clinical trials as monotherapy or in combination with cytotoxic chemotherapy. This review summarizes the most recent advances with the targeted therapies in the treatment of patients with advanced pancreatic cancer.
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Affiliation(s)
- Akintunde Akinleye
- Division of Hematology/Oncology, Department of Medicine, New York Medical College, Valhalla, New York, United States
| | - Chaitanya Iragavarapu
- Division of Hematology/Oncology, Department of Medicine, New York Medical College, Valhalla, New York, United States
| | - Muhammad Furqan
- Division of Hematology/Oncology, Department of Medicine, University of Iowa, Iowa City, Iowa, United States
| | - Shundong Cang
- Department of Oncology, Henan Province People's Hospital, Zhengzhou University, Zhengzhou, China
| | - Delong Liu
- Department of Oncology, Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
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15
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Yuan K, Yong S, Xu F, Zhou T, McDonald JM, Chen Y. Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer. Oncotarget 2015; 6:25308-19. [PMID: 26320171 PMCID: PMC4694833 DOI: 10.18632/oncotarget.4490] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 06/30/2015] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer is highly malignant with limited therapy and a poor prognosis. TRAIL-activating therapy has been promising, however, clinical trials have shown resistance and limited responses of pancreatic cancers. We investigated the effects of calmodulin(CaM) antagonists, trifluoperazine(TFP) and tamoxifen(TMX), on TRA-8-induced apoptosis and tumorigenesis of TRA-8-resistant pancreatic cancer cells, and underlying mechanisms. TFP or TMX alone did not induce apoptosis of resistant PANC-1 cells, while they dose-dependently enhanced TRA-8-induced apoptosis. TMX treatment enhanced efficacy of TRA-8 therapy on tumorigenesis in vivo. Analysis of TRA-8-induced death-inducing-signaling-complex (DISC) identified recruitment of survival signals, CaM/Src, into DR5-associated DISC, which was inhibited by TMX/TFP. In contrast, TMX/TFP increased TRA-8-induced DISC recruitment/activation of caspase-8. Consistently, caspase-8 inhibition blocked the effects of TFP/TMX on TRA-8-induced apoptosis. Moreover, TFP/TMX induced DR5 expression. With a series of deletion/point mutants, we identified CaM antagonist-responsive region in the putative Sp1-binding domain between -295 to -300 base pairs of DR5 gene. Altogether, we have demonstrated that CaM antagonists enhance TRA-8-induced apoptosis of TRA-8-resistant pancreatic cancer cells by increasing DR5 expression and enhancing recruitment of apoptotic signal while decreasing survival signals in DR5-associated DISC. Our studies support the use of these readily available CaM antagonists combined with TRAIL-activating agents for pancreatic cancer therapy.
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Affiliation(s)
- Kaiyu Yuan
- Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
| | - Sun Yong
- Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
| | - Fei Xu
- Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
| | - Tong Zhou
- Department of Medicine, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
| | - Jay M McDonald
- Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
- Birmingham Veterans Affairs Medical Center, Alabama 35294, Birmingham, USA
| | - Yabing Chen
- Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
- Birmingham Veterans Affairs Medical Center, Alabama 35294, Birmingham, USA
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16
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Tanaka R, Tomosugi M, Horinaka M, Sowa Y, Sakai T. Metformin Causes G1-Phase Arrest via Down-Regulation of MiR-221 and Enhances TRAIL Sensitivity through DR5 Up-Regulation in Pancreatic Cancer Cells. PLoS One 2015; 10:e0125779. [PMID: 25955843 PMCID: PMC4425682 DOI: 10.1371/journal.pone.0125779] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 03/25/2015] [Indexed: 12/30/2022] Open
Abstract
Although many chemotherapeutic strategies against cancer have been developed, pancreatic cancer is one of the most aggressive and intractable types of malignancies. Therefore, new strategies and anti-cancer agents are necessary to treat this disease. Metformin is a widely used drug for type-2 diabetes, and is also known as a promising candidate anti-cancer agent from recent studies in vitro and in vivo. However, the mechanisms of metformin's anti-cancer effects have not been elucidated. We demonstrated that metformin suppressed the expression of miR-221, one of the most well-known oncogenic microRNAs, in human pancreatic cancer PANC-1 cells. Moreover, we showed that the down-regulation of miR-221 by metformin caused G1-phase arrest via the up-regulation of p27, one of the direct targets of miR-221. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is also a promising agent for cancer treatment. While recent studies showed that treatment with only TRAIL was not effective against pancreatic cancer cells, the present data showed that metformin sensitized p53-mutated pancreatic cancer cells to TRAIL. Metformin induced the expressions of death receptor 5 (DR5), a receptor for TRAIL, and Bim with a pro-apoptotic function in the downstream of TRAIL-DR5 pathway. We suggest that the up-regulation of these proteins may contribute to sensitization of TRAIL-induced apoptosis. The combination therapy of metformin and TRAIL could therefore be effective in the treatment of pancreatic cancer.
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Affiliation(s)
- Ryoichi Tanaka
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mitsuhiro Tomosugi
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mano Horinaka
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
- * E-mail:
| | - Yoshihiro Sowa
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiyuki Sakai
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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von Karstedt S, Conti A, Nobis M, Montinaro A, Hartwig T, Lemke J, Legler K, Annewanter F, Campbell AD, Taraborrelli L, Grosse-Wilde A, Coy JF, El-Bahrawy MA, Bergmann F, Koschny R, Werner J, Ganten TM, Schweiger T, Hoetzenecker K, Kenessey I, Hegedüs B, Bergmann M, Hauser C, Egberts JH, Becker T, Röcken C, Kalthoff H, Trauzold A, Anderson KI, Sansom OJ, Walczak H. Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. Cancer Cell 2015; 27:561-73. [PMID: 25843002 PMCID: PMC6591140 DOI: 10.1016/j.ccell.2015.02.014] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 02/02/2015] [Accepted: 02/26/2015] [Indexed: 01/05/2023]
Abstract
Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.
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Affiliation(s)
- Silvia von Karstedt
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
| | - Annalisa Conti
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK; Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Max Nobis
- Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Antonella Montinaro
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
| | - Torsten Hartwig
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
| | - Johannes Lemke
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
| | - Karen Legler
- Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany
| | - Franka Annewanter
- Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany
| | - Andrew D Campbell
- Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Lucia Taraborrelli
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
| | - Anne Grosse-Wilde
- German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA
| | - Johannes F Coy
- German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; TAVARLIN AG, Biotechpark Pfungstadt, Reißstraße 1a, 64319 Pfungstadt, Germany
| | - Mona A El-Bahrawy
- Department of Histopathology, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - Frank Bergmann
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
| | - Ronald Koschny
- Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Jens Werner
- Department of Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Tom M Ganten
- Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Thomas Schweiger
- Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Konrad Hoetzenecker
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Istvan Kenessey
- 2nd Department of Pathology, Semmelweis University Budapest, Ulloi ut 93, 1091 Budapest, Hungary
| | - Balazs Hegedüs
- Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, 1091 Budapest, Hungary
| | - Michael Bergmann
- Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Charlotte Hauser
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Jan-Hendrik Egberts
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Thomas Becker
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Holger Kalthoff
- Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany
| | - Anna Trauzold
- Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany; Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Kurt I Anderson
- Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Owen J Sansom
- Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Henning Walczak
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
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Byeon HJ, Kim I, Choi JS, Lee ES, Shin BS, Youn YS. PEGylated apoptotic protein-loaded PLGA microspheres for cancer therapy. Int J Nanomedicine 2015; 10:739-48. [PMID: 25632232 PMCID: PMC4304599 DOI: 10.2147/ijn.s75821] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The aim of the current study was to investigate the antitumor potential of poly (D,L-lactic-co-glycolic acid) microspheres (PLGA MSs) containing polyethylene glycol (PEG)-conjugated (PEGylated) tumor necrosis factor–related apoptosis-inducing ligand (PEG-TRAIL). PEG-TRAIL PLGA MSs were prepared by using a water-in-oil-in-water double-emulsion method, and the apoptotic activities of supernatants released from the PLGA MSs at days 1, 3, and 7 were examined. The antitumor effect caused by PEG-TRAIL PLGA MSs was evaluated in pancreatic Mia Paca-2 cell-xenografted mice. PEG-TRAIL PLGA MS was found to be spherical and 14.4±1.06 μm in size, and its encapsulation efficiency was significantly greater than that of TRAIL MS (85.7%±4.1% vs 43.3%±10.9%, respectively). The PLGA MS gradually released PEG-TRAIL for 14 days, and the released PEG-TRAIL was shown to have clear apoptotic activity in Mia Paca-2 cells, whereas TRAIL released after 1 day had a negligible activity. Finally, PEG-TRAIL PLGA MS displayed remarkably greater antitumor efficacy than blank or TRAIL PLGA MS in Mia Paca-2 cell-xenografted mice in terms of tumor volume and weight, apparently due to increased stability and well-retained apoptotic activity of PEG-TRAIL in PLGA MS. We believe that this PLGA MS system, combined with PEG-TRAIL, should be considered a promising candidate for treating pancreatic cancer.
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Affiliation(s)
- Hyeong Jun Byeon
- Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Insoo Kim
- Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ji Su Choi
- Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Eun Seong Lee
- Division of Biotechnology, The Catholic University of Korea, Bucheon-si, Republic of Korea
| | - Beom Soo Shin
- Department of Pharmacy, College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Republic of Korea
| | - Yu Seok Youn
- Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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Wachsmann MB, Pop LM, Vitetta ES. Pancreatic ductal adenocarcinoma: a review of immunologic aspects. J Investig Med 2014. [PMID: 22406516 DOI: 10.231/jim.0b013e31824a4d79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
With the continued failures of both early diagnosis and treatment options for pancreatic cancer, it is now time to comprehensively evaluate the role of the immune system on the development and progression of pancreatic cancer. It is important to develop strategies that harness the molecules and cells of the immune system to treat this disease. This review will focus primarily on the role of immune cells in the development and progression of pancreatic ductal adenocarcinoma and to evaluate what is known about the interaction of immune cells with the tumor microenvironment and their role in tumor growth and metastasis. We will conclude with a brief discussion of therapy for pancreatic cancer and the potential role for immunotherapy. We hypothesize that the role of the immune system in tumor development and progression is tissue specific. Our hope is that better understanding of this process will lead to better treatments for this devastating disease.
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Affiliation(s)
- Megan B Wachsmann
- Masters Program in Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Byeon HJ, Choi SH, Choi JS, Kim I, Shin BS, Lee ES, Park ES, Lee KC, Youn YS. Four-arm PEG cross-linked hyaluronic acid hydrogels containing PEGylated apoptotic TRAIL protein for treating pancreatic cancer. Acta Biomater 2014; 10:142-50. [PMID: 24021228 DOI: 10.1016/j.actbio.2013.08.046] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 08/02/2013] [Accepted: 08/29/2013] [Indexed: 01/29/2023]
Abstract
Four-arm polyethylene glycol (PEG) cross-linked hyaluronic acid (HA) hydrogels containing PEGylated tumor necrosis factor-related apoptosis-inducing ligand (PEG-TRAIL) were fabricated, and their antitumor effects were evaluated in pancreatic cell (Mia Paca-2)-xenografted mice. HA was conjugated with 4-arm PEG(10k)-amine (a cross-linker) at ratios of 100:1 and 100:2 using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a cross-linker, and TRAIL or PEG-TRAIL was incorporated into these HA hydrogels. HA hydrogels at a 100:1 ratio were prepared in good yields (>88%), were moderately stiff, and gradually released PEG-TRAIL over ~14 days in vitro and over ~7 days in vivo (as determined by high-pressure liquid chromatography and infrared imaging). The released PEG-TRAIL was found to have obvious apoptotic activity in Mia Paca-2 cells. PEG-TRAIL HA hydrogels displayed remarkably more antitumor efficacy than TRAIL HA hydrogels in Mia Paca-2 cell-xenografted mice in terms of tumor volumes (size) and weights (453.2mm(3) and 1.03 g vs. 867.5mm(3) and 1.86 g). Furthermore, this improved antitumor efficacy was found to be due to the apoptotic activity of PEG-TRAIL in vivo (determined by a TUNEL assay) despite its substantially lower cytotoxicity than native TRAIL (IC50 values: 71.8 and 202.5 ng ml(-1), respectively). This overall enhanced antitumor effect of PEG-TRAIL HA hydrogels appeared to be due to the increased stability of PEGylated TRAIL in HA hydrogels. These findings indicate that this HA hydrogel system combined with PEG-TRAIL should be considered a potential candidate for the treatment of pancreatic cancer.
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Affiliation(s)
- Hyeong Jun Byeon
- School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea
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Byeon HJ, Choi SH, Choi JS, Kim TH, Lee ES, Lee KC, Youn YS. Apoptotic activity and antitumor efficacy of PEGylated TNF-related apoptosis-inducing ligand (TRAIL) in a Mia Paca-2 cell-xenografted mouse model. Biomed Pharmacother 2013; 68:65-9. [PMID: 24268811 DOI: 10.1016/j.biopha.2013.10.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 10/24/2013] [Indexed: 01/29/2023] Open
Abstract
The purpose of this study was to demonstrate the apoptotic activity and antitumor effect of PEGylated tumor necrosis factor-related apoptosis-inducing ligand (PEG-TRAIL) in pancreatic carcinoma Mia Paca-2 cells and in Mia Paca-2 cell-xenografted mice. PEG-TRAIL was prepared using mPEG-aldehyde (Mw 5 kDa). The apoptosis induced by PEG-TRAIL in Mia Paca-2 cells and in the tumors of Mia Paca-2 cell-xenografted mice was quantified by FACS analysis and using a TUNEL assay. Mia Paca-2 cell-xenografted BALB/c nu/nu mice were administered intratumoral injections of PEG-TRAIL (50 μg/mouse/injection) every 3 days from day 0 (~4 weeks after xenografting) to day 15. Tumor volumes were measured every 3 days from day 0 to day 27. PEG-TRAIL displayed obvious apoptotic activity in Mia Paca-2 cells; the FACS signal was shifted to the apoptotic area and the cells exhibited green fluorescence indicating apoptosis in the TUNEL assay. Furthermore, PEG-TRAIL was found to suppress tumors in Mia Paca-2 cell-xenografted mice (tumor volumes: 183.9±134.1 for PEG-TRAIL vs. 1827.3±264.5 mm(3) for saline control). In addition, in vivo TUNEL assays of tumor tissues showed that the antitumor effect of PEG-TRAIL was due apoptosis. Our findings provide clear in vivo evidence of the antitumor potential of PEG-TRAIL in a Mia Paca-2 cell-xenografted mouse model based of pancreatic cancer.
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Affiliation(s)
- Hyeong Jun Byeon
- School of Pharmacy, Sungkyunkwan University, 300, Cheoncheon-dong, Jangan-gu, 440-746 Suwon, Republic of Korea
| | - Seong Ho Choi
- School of Pharmacy, Sungkyunkwan University, 300, Cheoncheon-dong, Jangan-gu, 440-746 Suwon, Republic of Korea
| | - Ji Su Choi
- School of Pharmacy, Sungkyunkwan University, 300, Cheoncheon-dong, Jangan-gu, 440-746 Suwon, Republic of Korea
| | - Tae Hyung Kim
- School of Pharmacy, Sungkyunkwan University, 300, Cheoncheon-dong, Jangan-gu, 440-746 Suwon, Republic of Korea
| | - Eun Seong Lee
- Division of Biotechnology, The Catholic University of Korea, 43-1, Yeokgok 2-dong, Wonmi-gu, Bucheon-si, 420-743 Gyeonggi-do, Republic of Korea
| | - Kang Choon Lee
- School of Pharmacy, Sungkyunkwan University, 300, Cheoncheon-dong, Jangan-gu, 440-746 Suwon, Republic of Korea
| | - Yu Seok Youn
- School of Pharmacy, Sungkyunkwan University, 300, Cheoncheon-dong, Jangan-gu, 440-746 Suwon, Republic of Korea.
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Gottwald L, Szwalski J, Piekarski J, Pasz-Walczak G, Kubiak R, Spych M, Suzin J, Tyliński W, Sęk P, Jeziorski A. Membrane expression of the death ligand trail receptors DR4 and DR5 in the normal endometrium, endometrial atypical hyperplasia and endometrioid endometrial cancer. J OBSTET GYNAECOL 2013; 33:512-8. [PMID: 23815209 DOI: 10.3109/01443615.2013.790886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
To assess membrane expression of DR4 and DR5 in the normal endometrium (NE), endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC), the study examined 101 patients: 20 NE, 14 EAH and 67 EEC. The expression of DR4 and DR5 was examined and presented as the total score (TS). DR4 expression was seen in 18 NE, 11 EAH and 10 EEC. DR5 expression was seen in 20 NE, 13 EAH and 21 EEC. A strong correlation between type of endometrial tissue and TS of both receptors was identified. In EEC TS of DR4 and DR5 was not related to grading, staging or survival. Malignant transformation in the endometrium is related to reduction of membrane DR4 and DR5 expression. The level of membrane staining of the receptors in EEC is not dependent on grading and staging, and is not sufficient to predict survival in EEC patients.
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Affiliation(s)
- L Gottwald
- Department of Radiotherapy, Medical University of Lodz, ul. Paderewskiego 4, 93 – 509 Lodz, Poland.
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23
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Membrane expression of TRAIL receptors DR4, DR5, DcR1 and DcR2 in the normal endometrium, atypical endometrial hyperplasia and endometrioid adenocarcinoma: a tissue microarray study. Arch Gynecol Obstet 2013; 288:889-99. [PMID: 23584885 PMCID: PMC3778234 DOI: 10.1007/s00404-013-2840-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Accepted: 04/01/2013] [Indexed: 01/09/2023]
Abstract
Purpose To evaluate the membrane expression of DR4, DR5, DcR1 and DcR2 in the normal endometrium (NE), atypical endometrial hyperplasia (AEH) and endometrioid adenocarcinoma (EAC). Methods The study comprised 197 patients: 20 NE, 18 AEH and 159 EAC. Tissue microarrays were constructed. Membrane expression of DR4, DR5, DcR1 and DcR2 was examined and presented as total score (TS). Results In EAC, the membrane expression of DR4, DR5 and DcR2 was less common compared to NE (p < 0.001; p < 0.001; p = 0.018) and AEH (p < 0.001; p < 0.001; p = 0.004). In EAC the membrane expression of DcR1 did not differ when compared to NE (p = 0.055) and AEH (p = 0.173). A strong correlation was found between the type of endometrial tissue (NE/AEH/EAC) and the TS of DR4 (p < 0.001), DR5 (p < 0.001), DcR1 (p = 0.033) and DcR2 (p < 0.001). In EAC, the TS of DR4, DR5, DcR1 and DcR2 was not related to grading and staging. In EAC, the membrane expression of DR5, but not DR4, DcR1 and DcR2, was related to better disease-free survival (DFS). The overall survival (OS) was not related to membrane TRAIL receptors expression. Conclusions The membrane expression of the receptors for TRAIL DR4, DR5, DcR1 and DcR2 is greater in NE than EAC. The level of membrane staining of the receptors in EAC is not dependent on grading and staging. In EAC patients, membrane expression of DR4, DR5, DcR1 and DcR2 are not independent predictors of survival.
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Chen CY, Tsai MM, Chi HC, Lin KH. Biological significance of a thyroid hormone-regulated secretome. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2013; 1834:2271-84. [PMID: 23429180 DOI: 10.1016/j.bbapap.2013.02.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 02/07/2013] [Accepted: 02/11/2013] [Indexed: 01/18/2023]
Abstract
The thyroid hormone, 3,3,5-triiodo-L-thyronine (T3), modulates several physiological processes, including cellular growth, differentiation, metabolism and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Several intracellular and extracellular protein candidates are regulated by T3. Moreover, T3-regulated secreted proteins participate in physiological processes or cellular transformation. T3 has been employed as a marker in several disorders, such as cardiovascular disorder in chronic kidney disease, as well as diseases of the liver, immune system, endocrine hormone metabolism and coronary artery. Our group subsequently showed that T3 regulates several tumor-related secretory proteins, leading to cancer progression via alterations in extracellular matrix proteases and tumor-associated signaling pathways in hepatocellular carcinomas. Therefore, elucidation of T3/thyroid hormone receptor-regulated secretory proteins and their underlying mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a detailed summary on the known secretory proteins regulated by T3 and their physiological significance. This article is part of a Special Issue entitled: An Updated Secretome.
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Affiliation(s)
- Cheng-Yi Chen
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
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25
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Yee NS. Toward the goal of personalized therapy in pancreatic cancer by targeting the molecular phenotype. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 779:91-143. [PMID: 23288637 DOI: 10.1007/978-1-4614-6176-0_5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The purpose of this article is to provide a critical review of the molecular alterations in pancreatic cancer that are clinically investigated as therapeutic targets and their potential impact on clinical outcomes. Adenocarcinoma of exocrine pancreas is generally associated with poor prognosis and the conventional therapies are marginally effective. Advances in understanding the genetic regulation of normal and neoplastic development of pancreas have led to development and clinical evaluation of new therapeutic strategies that target the signaling pathways and molecular alterations in pancreatic cancer. Applications have begun to utilize the genetic targets as biomarkers for prediction of therapeutic responses and selection of treatment options. The goal of accomplishing personalized tumor-specific therapy with tolerable side effects for patients with pancreatic cancer is hopefully within reach in the foreseeable future.
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Affiliation(s)
- Nelson S Yee
- Division of Hematology-Oncology, Department of Medicine, Penn State College of Medicine, Penn State Hershey Cancer Institute, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033-0850, USA.
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26
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Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, Rocha-Lima CM, Safran H, Chan D, Kocs DM, Galimi F, McGreivy J, Bray SL, Hei Y, Feigal EG, Loh E, Fuchs CS. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol 2012; 23:2834-2842. [PMID: 22700995 DOI: 10.1093/annonc/mds142] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.
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Affiliation(s)
- H L Kindler
- Section of Hematology/Oncology, University of Chicago Medical Center, Chicago.
| | | | | | - E B Garon
- David Geffen School of Medicine at University of California Los Angeles/Translational Oncology Research International Network, Los Angeles
| | - J J Stephenson
- Department of Experimental Therapeutics, Greenville Hospital System University Medical Center, Greenville
| | - C M Rocha-Lima
- Department of Medicine, University of Miami/Sylvester Comprehensive Cancer Center, Miami
| | - H Safran
- The Brown University Oncology Group, Rhode Island Hospital, Providence
| | - D Chan
- Cancer Care Associates Medical Group, Inc., Redondo Beach
| | - D M Kocs
- US Oncology Research, Round Rock
| | - F Galimi
- Global Development, Amgen Inc., Thousand Oaks
| | - J McGreivy
- Global Development, Amgen Inc., South San Francisco, USA
| | - S L Bray
- Department of Biostatistics and Epidemiology, Amgen Ltd, Cambridge, UK
| | - Y Hei
- Global Development, Amgen Inc., Thousand Oaks
| | - E G Feigal
- Global Development, Amgen Inc., Thousand Oaks
| | - E Loh
- Global Development, Amgen Inc., South San Francisco, USA
| | - C S Fuchs
- Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA
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27
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Shankar S, Marsh L, Srivastava RK. EGCG inhibits growth of human pancreatic tumors orthotopically implanted in Balb C nude mice through modulation of FKHRL1/FOXO3a and neuropilin. Mol Cell Biochem 2012; 372:83-94. [PMID: 22971992 DOI: 10.1007/s11010-012-1448-y] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2012] [Accepted: 08/31/2012] [Indexed: 12/13/2022]
Abstract
Human pancreatic cancer is currently one of the fourth leading causes of cancer-related mortality with a 5-year survival rate of less than 5 %. Since pancreatic carcinoma is largely refractory to conventional therapies, there is a strong medical need for the development of novel and innovative cancer preventive strategies. The forkhead transcription factors of the O class (FOXO) play a major role in cell proliferation, angiogenesis, metastasis, and tumorigenesis. The objectives of this study were to examine whether FKHRL1/FOXO3a modulates antitumor activity of (-)-epigallocatechin-3-gallate (EGCG), an active ingredient in green tea, in pancreatic cancer model in vivo. PANC-1 cells were orthotopically implanted into Balb c nude mice and gavaged with EGCG after tumor formation. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of PI3K, AKT, ERK, and FOXO3a/FKHRL1 and its target genes were measured by the western blot analysis and/or q-RT-PCR. FOXO-DNA binding was measured by gel shift assay. EGCG-treated mice showed significant inhibition in tumor growth which was associated with reduced phosphorylation of ERK, PI3K, AKT, and FKHRL1/FOXO3a, and modulation of FOXO target genes. EGCG induced apoptosis by upregulating Bim and activating caspase-3. EGCG modulated markers of cell cycle (p27/KIP1), angiogenesis (CD31, VEGF, IL-6, IL-8, SEMA3F, and HIF1α), and metastasis (MMP2 and MMP7). The inhibition of VEGF by EGCG was associated with suppression of neuropilin. EGCG inhibited epithelial-mesenchymal transition by upregulating the expression of E-cadherin and inhibiting the expression of N-cadherin and Zeb1. These data suggest that EGCG inhibits pancreatic cancer orthotopic tumor growth, angiogenesis, and metastasis which are associated with inhibition of PI3K/AKT and ERK pathways and activation of FKHRL1/FOXO3a. As a conclusion, EGCG can be used for the prevention and/or treatment of pancreatic cancer.
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MESH Headings
- Animals
- Antineoplastic Agents, Phytogenic/pharmacology
- Apoptosis/drug effects
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/blood supply
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Catechin/analogs & derivatives
- Catechin/pharmacology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Forkhead Box Protein O3
- Forkhead Transcription Factors/metabolism
- Gene Expression/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- MAP Kinase Signaling System/drug effects
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neovascularization, Pathologic/prevention & control
- Neuropilins/metabolism
- Pancreas/pathology
- Pancreatic Neoplasms/blood supply
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Proliferating Cell Nuclear Antigen/metabolism
- Tumor Burden/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Sharmila Shankar
- Department of Pathology and Laboratory Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
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28
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Mamaghani S, Simpson CD, Cao PM, Cheung M, Chow S, Bandarchi B, Schimmer AD, Hedley DW. Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to TRAIL-induced apoptosis. PLoS One 2012; 7:e41102. [PMID: 22829912 PMCID: PMC3400624 DOI: 10.1371/journal.pone.0041102] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 06/21/2012] [Indexed: 12/16/2022] Open
Abstract
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis in a variety of cancer cell lines with little or no effect on normal cells. However, its effect is limited as some cancers including pancreatic cancer show de novo resistance to TRAIL induced apoptosis. In this study we report that GSK-3 inhibition using the pharmacologic agent AR-18, enhanced TRAIL sensitivity in a range of pancreatic and prostate cancer cell lines. This sensitization was found to be caspase-dependent, and both pharmacological and genetic knock-down of GSK-3 isoforms resulted in apoptotic features as shown by cleavage of PARP and caspase-3. Elevated levels of reactive oxygen intermediates and disturbance of mitochondrial membrane potential point to a mitochondrial amplification loop for TRAIL-induced apoptosis after GSK-3 inhibition. Consistent with this, overexpression of anti-apoptotic mitochondrial targets such as Bcl-XL, Mcl-1, and Bcl-2 rescued PANC-1 and PPC-1 cells from TRAIL sensitization. However, overexpression of the caspase-8 inhibitor CrmA also inhibited the sensitizing effects of GSK-3 inhibitor, suggesting an additional role for GSK-3 that inhibits death receptor signaling. Acute treatment of mice bearing PANC-1 xenografts with a combination of AR-18 and TRAIL also resulted in a significant increase in apoptosis, as measured by caspase-3 cleavage. Sensitization to TRAIL occurred despite an increase in β-catenin due to GSK-3 inhibition, suggesting that the approach might be effective even in cancers with dysregulated β-catenin. These results suggest that GSK-3 inhibitors might be effectively combined with TRAIL for the treatment of pancreatic cancer.
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Affiliation(s)
- Shadi Mamaghani
- Division of Applied Molecular Oncology, University Health Network, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Craig D. Simpson
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Pinjiang M. Cao
- Division of Applied Molecular Oncology, University Health Network, Toronto, Ontario, Canada
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - May Cheung
- Division of Applied Molecular Oncology, University Health Network, Toronto, Ontario, Canada
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Sue Chow
- Division of Applied Molecular Oncology, University Health Network, Toronto, Ontario, Canada
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Bizhan Bandarchi
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Aaron D. Schimmer
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
- Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - David W. Hedley
- Division of Applied Molecular Oncology, University Health Network, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada
- Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada
- * E-mail:
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29
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Chi HC, Chen SL, Liao CJ, Liao CH, Tsai MM, Lin YH, Huang YH, Yeh CT, Wu SM, Tseng YH, Chen CY, Tsai CY, Chung IH, Chen WJ, Lin KH. Thyroid hormone receptors promote metastasis of human hepatoma cells via regulation of TRAIL. Cell Death Differ 2012; 19:1802-14. [PMID: 22576662 DOI: 10.1038/cdd.2012.58] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although accumulating evidence has confirmed the important roles of thyroid hormone (T(3)) and its receptors (TRs) in tumor progression, the specific functions of TRs in carcinogenesis remain unclear. In the present study, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was directly upregulated by T(3) in TR-overexpressing hepatoma cell lines. TRAIL is an apoptotic inducer, but it can nonetheless trigger non-apoptotic signals favoring tumorigenesis in apoptosis-resistant cancer cells. We found that TR-overexpressing hepatoma cells treated with T(3) were apoptosis resistant, even when TRAIL was upregulated. This apoptotic resistance may be attributable to simultaneous upregulation of Bcl-xL by T(3), because (1) knockdown of T(3)-induced Bcl-xL expression suppressed T(3)-mediated protection against apoptosis, and (2) overexpression of Bcl-xL further protected hepatoma cells from TRAIL-induced apoptotic death, consequently leading to TRAIL-promoted metastasis of hepatoma cells. Moreover, T(3)-enhanced metastasis in vivo was repressed by the treatment of TRAIL-blocking antibody. Notably, TRAIL was highly expressed in a subset of hepatocellular carcinoma (HCC) patients, and this high-level expression was significantly correlated with that of TRs in these HCC tissues. Together, our findings provide evidence for the existence of a novel mechanistic link between increased TR and TRAIL levels in HCC. Thus, TRs induce TRAIL expression, and TRAIL thus synthesized acts in concert with simultaneously synthesized Bcl-xL to promote metastasis, but not apoptosis.
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Affiliation(s)
- H-C Chi
- Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan
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Abstract
With the continued failures of both early diagnosis and treatment options for pancreatic cancer, it is now time to comprehensively evaluate the role of the immune system on the development and progression of pancreatic cancer. It is important to develop strategies that harness the molecules and cells of the immune system to treat this disease. This review will focus primarily on the role of immune cells in the development and progression of pancreatic ductal adenocarcinoma and to evaluate what is known about the interaction of immune cells with the tumor microenvironment and their role in tumor growth and metastasis. We will conclude with a brief discussion of therapy for pancreatic cancer and the potential role for immunotherapy. We hypothesize that the role of the immune system in tumor development and progression is tissue specific. Our hope is that better understanding of this process will lead to better treatments for this devastating disease.
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Affiliation(s)
- Megan B. Wachsmann
- Masters Program in Clinical Sciences, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd, Dallas, Texas 75390-8576, USA
| | - Laurentiu M. Pop
- The Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd, Dallas, Texas 75390-8576, USA
| | - Ellen S. Vitetta
- The Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd, Dallas, Texas 75390-8576, USA
- The Departments of Microbiology and Immunology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd, Dallas, Texas 75390-8576, USA
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31
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Niu Y, Li Y, Zang J, Huang H, Deng J, Cui Z, Yu D, Deng J. Death receptor 5 and neuroproliferation. Cell Mol Neurobiol 2012; 32:255-65. [PMID: 21938487 PMCID: PMC11498502 DOI: 10.1007/s10571-011-9757-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 09/08/2011] [Indexed: 02/06/2023]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand is a member of the tumor necrosis factor superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). However, DR5 is also expressed in the developing CNS where it appears to play a role unrelated to apoptosis, and instead may be involved in the regulation of neurogenesis. We report on the distribution of DR5 expression in mouse hippocampus, cerebellum, and rostral migratory stream (RMS) of olfactory bulb from embryonic (E) day 16 (E16) to postnatal (P) day (P180). At E16, DR5-positive cells were distributed widely in embryonic hippocampus with strong immunostaining in the developing dentate gyrus. In newborn hippocampus, DR5-positive cells were predominantly located in proliferative zones, such as dentate gyrus, subventricular zone, and RMS. After postnatal day 7 (P7), the number of DR5-positive cells decreased, and cells with intense fluorescence were primarily restricted to the subgranular layer (SGL), although the granular cell layer showed weak fluorescence. After P30, only few DR5-positive cells were found in SGL, and mature granule cells were negative for DR5 expression. To address whether DR5 expression is a restricted to progenitor cells and newborn neurons, we performed 5-bromo-deoxyuridine labeling. We report that proliferative cells in the SGL selectively express DR5, with lower levels of expression in cells positive for doublecortin, a marker of newborn neurons. In addition, the stem cells in intestine, cerebellum, and RMS were also demonstrated to be DR5-positive. In the meantime, in cerebellum, DR5-positive cells were also positive for glial fibrillary acidic protein, a marker of proliferative Bergmann cells. We conclude that DR5 is selectively expressed by neuroprogenitor cells and newborn neurons, suggesting that the DR5 death receptor is likely to play a key role in neuroproliferation and differentiation.
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Affiliation(s)
- Yanli Niu
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Yongqiang Li
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Jianfeng Zang
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Hongen Huang
- Jiujiang Traditional Hospital, Jiujiang, 332000 China
| | - Jiexin Deng
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Zhanjun Cui
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Dongming Yu
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Jinbo Deng
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
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32
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Pérez-Torras S, Vidal-Pla A, Miquel R, Almendro V, Fernández-Cruz L, Navarro S, Maurel J, Carbó N, Gascón P, Mazo A. Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening. Cell Oncol (Dordr) 2011; 34:511-21. [PMID: 21681527 DOI: 10.1007/s13402-011-0049-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2011] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. METHODS An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability. RESULTS Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models. CONCLUSIONS This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses.
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Affiliation(s)
- Sandra Pérez-Torras
- Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona, Spain
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Amm HM, Oliver PG, Lee CH, Li Y, Buchsbaum DJ. Combined modality therapy with TRAIL or agonistic death receptor antibodies. Cancer Biol Ther 2011; 11:431-49. [PMID: 21263219 PMCID: PMC3087899 DOI: 10.4161/cbt.11.5.14671] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Revised: 12/21/2010] [Accepted: 12/29/2010] [Indexed: 12/20/2022] Open
Abstract
Molecularly targeted therapies, such as antibodies and small molecule inhibitors have emerged as an important breakthrough in the treatment of many human cancers. One targeted therapy under development is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) due to its ability to induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in most normal cells. TRAIL and apoptosis-inducing agonistic antibodies to the TRAIL death receptors have been the subject of many preclinical and clinical studies in the past decade. However, the sensitivity of individual cancer cell lines of a particular tumor type to these agents varies from highly sensitive to resistant. Various chemotherapy agents have been shown to enhance the apoptosis-inducing capacity of TRAIL receptor-targeted therapies and induce sensitization of TRAIL-resistant cells. This review provides an overview of the mechanisms associated with chemotherapy enhancement of TRAIL receptor-targeted therapies including modulation of the apoptotic (death receptor expression, FLIP, and Bcl-2 or inhibitors of apoptosis (IAP) families) as well as cell signaling (NFκB, Akt, p53) pathways. These mechanisms will be important in establishing effective combinations to pursue clinically and in determining relevant targets for future cancer therapies.
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Affiliation(s)
- Hope M Amm
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA
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34
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Gatsinzi T, Iverfeldt K. Sensitization to TRAIL-induced apoptosis in human neuroblastoma SK-N-AS cells by NF-κB inhibitors is dependent on reactive oxygen species (ROS). J Neurooncol 2011; 104:459-72. [DOI: 10.1007/s11060-010-0516-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Accepted: 12/20/2010] [Indexed: 01/24/2023]
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Fulda S. Targeting apoptosis signaling in pancreatic cancer. Cancers (Basel) 2011; 3:241-51. [PMID: 24212616 PMCID: PMC3756359 DOI: 10.3390/cancers3010241] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Revised: 01/05/2011] [Accepted: 01/06/2011] [Indexed: 12/14/2022] Open
Abstract
The ability to escape apoptosis or programmed cell death is a hallmark of human cancers, for example pancreatic cancer. This can promote tumorigenesis, since too little cell death by apoptosis disturbs tissue homeostasis. Additionally, defective apoptosis signaling is the underlying cause of failure to respond to current treatment approaches, since therapy-mediated antitumor activity requires the intactness of apoptosis signaling pathways in cancer cells. Thus, the elucidation of defects in the regulation of apoptosis in pancreatic carcinoma can result in the identification of novel targets for therapeutic interference and for exploitation for cancer drug discovery.
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Affiliation(s)
- Simone Fulda
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany.
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36
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Rajeshkumar NV, Rasheed ZA, García-García E, López-Ríos F, Fujiwara K, Matsui WH, Hidalgo M. A combination of DR5 agonistic monoclonal antibody with gemcitabine targets pancreatic cancer stem cells and results in long-term disease control in human pancreatic cancer model. Mol Cancer Ther 2010; 9:2582-92. [PMID: 20660600 DOI: 10.1158/1535-7163.mct-10-0370] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with one of the worst outcomes among all cancers. PDA often recurs after initial treatment to result in patient death despite the use of chemotherapy or radiation therapy. PDA contains a subset of tumor-initiating cells capable of extensive self-renewal known as cancer stem cells (CSC), which may contribute to therapeutic resistance and metastasis. At present, conventional chemotherapy and radiotherapy are largely ineffective in depleting CSC pool, suggesting the need for novel therapies that specifically target the cancer-sustaining stem cells for tumor eradication and to improve the poor prognosis of PDA patients. In this study, we report that death receptor 5 (DR5) is enriched in pancreatic CSCs compared with the bulk of the tumor cells. Treating a collection of freshly generated patient-derived PDA xenografts with gemcitabine, the first-line chemotherapeutic agent for PDA, is initially effective in reducing tumor size, but largely ineffective in diminishing the CSC populations, and eventually culminated in tumor relapse. However, a combination of tigatuzumab, a fully humanized DR5 agonist monoclonal antibody, with gemcitabine proved to be more efficacious by providing a double hit to kill both CSCs and bulk tumor cells. The combination therapy produced remarkable reduction in pancreatic CSCs, tumor remissions, and significant improvements in time to tumor progression in a model that is considered more difficult to treat. These data provide the rationale to explore the DR5-directed therapies in combination with chemotherapy as a therapeutic option to improve the current standard of care for pancreatic cancer patients.
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Affiliation(s)
- N V Rajeshkumar
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA.
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Schüler S, Fritsche P, Diersch S, Arlt A, Schmid RM, Saur D, Schneider G. HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells. Mol Cancer 2010; 9:80. [PMID: 20398369 PMCID: PMC2867820 DOI: 10.1186/1476-4598-9-80] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2009] [Accepted: 04/16/2010] [Indexed: 12/31/2022] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions. Results Depletion of HDAC2, but not HDAC1, in the pancreatic cancer cell lines MiaPaCa2 and Panc1 resulted in a marked sensitization towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Correspondingly, the more class I selective HDAC inhibitor (HDACI) valproic acid (VPA) synergized with TRAIL to induce apoptosis of MiaPaCa2 and Panc1 cells. At the molecular level, an increased expression of the TRAIL receptor 1 (DR5), accelerated processing of caspase 8, pronounced cleavage of the BH3-only protein Bid, and increased effector caspase activation was observed in HDAC2-depleted and TRAIL-treated MiaPaCa2 cells. Conclusions Our data characterize a novel HDAC2 function in PDAC cells and point to a strategy to overcome TRAIL resistance of PDAC cells, a prerequisite to succeed with a TRAIL targeted therapy in clinical settings.
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Affiliation(s)
- Susanne Schüler
- Technische Universität München, Klinikum rechts der Isar, II, Medizinische Klinik, Ismaninger Str, 22, 81675 Munich, Germany
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Kimotsuki T, Tanaka K, Sugiura T, Koyama K, Nakamura T, Kamimura Y, Takasaki W, Manabe S. Thirteen-week Intravenous Toxicity Study of a Novel Humanized Anti-Human Death Receptor 5 Monoclonal Antibody, CS-1008, in Cynomolgus Monkeys. J Toxicol Pathol 2010; 23:11-7. [PMID: 22272006 PMCID: PMC3234651 DOI: 10.1293/tox.23.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Accepted: 10/07/2009] [Indexed: 01/09/2023] Open
Abstract
CS-1008, a humanized monoclonal antibody that is agonistic to human death
receptor 5, was intravenously administered to cynomolgus monkeys twice a week
for 13 weeks at 3 different dose levels (5, 15 and 42 mg/kg) in order to
evaluate its potential toxicity. A control group received phosphate buffered
saline containing 0.01% polysorbate 80. Each of the 4 groups consisted of 3 male
and 3 female cynomolgus monkeys. No animal in any group died during the dosing
period. No toxic changes in clinical signs, food consumption, body weight,
electrocardiography, ophthalmology, urinalysis, hematology, blood chemistry,
gross pathology, organ weights or histopathology were noted in any group during
the dosing period. In the toxicokinetic analysis, the values for the maximum
concentration of CS-1008 in plasma and the area under the curve generally
increased with increasing dose. No clear differences in the toxicokinetic
parameters or profiles were observed between the sexes. Development of
anti-CS-1008 antibodies was not detected in any sample. The no-observed
adverse-effect level (NOAEL) of CS-1008 in cynomolgus monkeys under the
conditions of this study was concluded to be 42 mg/kg in both sexes, when
administered intravenously twice a week for 13 weeks. This study supports the
development of CS-1008 as a therapeutic biopharmaceutical.
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Affiliation(s)
- Tomofumi Kimotsuki
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co.,
Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan
| | - Kohji Tanaka
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co.,
Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan
| | - Tomomi Sugiura
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co.,
Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan
| | - Kumiko Koyama
- Drug Metabolism and Pharmacokinetics Research Laboratories,
Daiichi Sankyo Co., Ltd., 1–2–58 Hiromachi, Shinagawa-ku, Tokyo 140-8710,
Japan
| | - Takahiro Nakamura
- Drug Safety Research Laboratories, Shin Nippon Biomedical
Laboratories, Ltd., 2438 Miyanoura, Kagoshima 891-1394, Japan
| | - Yasuhiro Kamimura
- Drug Safety Research Laboratories, Shin Nippon Biomedical
Laboratories, Ltd., 2438 Miyanoura, Kagoshima 891-1394, Japan
| | - Wataru Takasaki
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co.,
Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan
| | - Sunao Manabe
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co.,
Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan
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Abstract
Pancreatic cancer represents a major challenge for research studies and clinical management. No specific tumor marker for the diagnosis of pancreatic cancer exists. Therefore, extensive genomic, transcriptomic, and proteomic studies are being developed to identify candidate markers for use in high-throughput systems capable of large cohort screening. Understandably, the complex pathophysiology of pancreatic cancer requires sensitive and specific biomarkers that can improve both early diagnosis and therapeutic monitoring. The lack of a single diagnostic marker makes it likely that only a panel of biomarkers is capable of providing the appropriate combination of high sensitivity and specificity. Biomarker discovery using novel technology can improve prognostic upgrading and pinpoint new molecular targets for innovative therapy.
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40
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Ganten TM, Sykora J, Koschny R, Batke E, Aulmann S, Mansmann U, Stremmel W, Sinn HP, Walczak H. Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer. J Mol Med (Berl) 2009; 87:995-1007. [PMID: 19680616 DOI: 10.1007/s00109-009-0510-z] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2007] [Revised: 06/24/2009] [Accepted: 07/17/2009] [Indexed: 01/02/2023]
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to TRAIL receptors 1 and 2 (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) have no or only a truncated cytoplasmic death domain. Consequently, they cannot induce apoptosis and instead have been proposed to inhibit apoptosis induction by TRAIL. Agonists for the apoptosis-inducing TRAIL-R1 and TRAIL-R2 are currently tested in clinical trials. To determine the expression pattern of all surface-bound TRAIL receptors and their prognostic clinical value, we investigated tumour samples of 311 patients with breast cancer by immunohistochemistry. TRAIL receptor expression profiles were correlated with clinico-pathological data, disease-free survival and overall survival. TRAIL-R1 was more strongly expressed in better differentiated tumours, and correlated positively with surrogate markers of a better prognosis (hormone receptor status, Bcl-2, negative nodal status), but negatively with the expression of Her2/neu and the proliferation marker Ki67. In contrast, TRAIL-R2 and TRAIL-R4 expression correlated with higher tumour grades, higher Ki67 index, higher Her2/neu expression and a positive nodal status at the time of diagnosis, but with lower expression of Bcl-2. Thus, the TRAIL receptor expression pattern was predictive of nodal status. Patients with grade 1 and 2 tumours, who had TRAIL-R2 but no TRAIL-R1, showed a positive lymph node status in 47% of the cases. Vice versa, only 19% had a positive nodal status with high TRAIL-R1 but low TRAIL-R2. Most strikingly, TRAIL-R4 and -R2 expression negatively correlated with overall survival of breast cancer patients. Although TRAIL-R2 correlated with more aggressive tumour behaviour, mammary carcinoma could be sensitised to TRAIL-R2-induced apoptosis, suggesting that TRAIL-R2 might therefore be used to therapeutically target such tumours. Hence, determination of the TRAIL receptor expression profile may aid in defining which breast cancer patients have a higher risk of lymph node metastasis and worse overall survival and on the other hand will help to guide TRAIL-based tumour therapy.
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Affiliation(s)
- Tom M Ganten
- Division of Apoptosis Regulation (D040), German Cancer Research Center (DKFZ), Heidelberg, Germany
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41
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Abstract
Resistance to apoptosis (programmed cell death) is a characteristic feature of human malignancies including pancreatic cancer, which is one of the leading causes of cancer deaths in the western world. Defects in this intrinsic cell death program can contribute to the multistep process of tumorigenesis, because too little cell death can disturb tissue homeostasis. Further, blockade of apoptosis pathways can cause treatment failure, because intact apoptosis signalling cascades largely mediate therapy-induced cytotoxicity. The elucidation of apoptosis pathways in pancreatic carcinoma over the last decade has resulted in the identification of various molecular defects. How apoptosis pathways can be exploited for the treatment of pancreatic cancer will be discussed in this review.
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Affiliation(s)
- Simone Fulda
- University Children's Hospital, Eythstr., Ulm, Germany.
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Sanlioglu AD, Dirice E, Elpek O, Korcum AF, Ozdogan M, Suleymanlar I, Balci MK, Griffith TS, Sanlioglu S. High TRAIL death receptor 4 and decoy receptor 2 expression correlates with significant cell death in pancreatic ductal adenocarcinoma patients. Pancreas 2009; 38:154-160. [PMID: 18981952 DOI: 10.1097/mpa.0b013e31818db9e3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES The importance of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor expression in pancreatic carcinoma development is not known. To reveal the putative connection of TRAIL and TRAIL receptor expression profile to this process, we analyzed and compared the expression profile of TRAIL and its receptors in pancreatic tissues of both noncancer patients and patients with pancreatic ductal adenocarcinoma (PDAC). METHODS Thirty-one noncancer patients and 34 PDAC patients were included in the study. TRAIL and TRAIL receptor expression profiles were determined by immunohistochemistry. Annexin V binding revealed the apoptotic index in pancreas. Lastly, the tumor grade, tumor stage, tumor diameter, perineural invasion, and number of lymph node metastasis were used for comparison purposes. RESULTS TRAIL decoy receptor 2 (DcR2) and death receptor 4 expression were up-regulated in PDAC patients compared with noncancer patients, and the ductal cells of PDAC patients displayed significant levels of apoptosis. In addition, acinar cells from PDAC patients had higher DcR2 expression but lower death receptor 4 expression. Increased DcR2 expression was also observed in Langerhans islets of PDAC patients. CONCLUSIONS Differential alteration of TRAIL and TRAIL receptor expression profiles in PDAC patients suggest that the TRAIL/TRAIL receptor system may play a pivotal role during pancreatic carcinoma development.
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Affiliation(s)
- Ahter Dilsad Sanlioglu
- Department of Medical Biology and Genetics, Faculty of Medicine, Human Gene Therapy Unit, Akdeniz University, Antalya, Turkey.
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Ahmed F, Ohtsuki T, Aida W, Ishibashi M. Tyrosine derivatives isolated from Streptomyces sp. IFM 10937 in a screening program for TRAIL-resistance-overcoming activity. JOURNAL OF NATURAL PRODUCTS 2008; 71:1963-1966. [PMID: 18847278 DOI: 10.1021/np8004248] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Exploration of actinomycetes for isolation of natural products for abrogating TRAIL resistance led to the isolation of two new tyrosine derivatives (1 and 2) along with novobiocin (3). The structures of 1 and 2 were determined by spectroscopic methods, while the absolute configuration was determined by analyzing CD spectra and by a modified Marfey's method. Compounds 1 (150 μM) and 3 (37.5 and 75 μM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma cells.
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Affiliation(s)
- Firoj Ahmed
- Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
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Kim H, Morgan DE, Buchsbaum DJ, Zeng H, Grizzle WE, Warram JM, Stockard CR, McNally LR, Long JW, Sellers JC, Forero A, Zinn KR. Early therapy evaluation of combined anti-death receptor 5 antibody and gemcitabine in orthotopic pancreatic tumor xenografts by diffusion-weighted magnetic resonance imaging. Cancer Res 2008; 68:8369-76. [PMID: 18922909 PMCID: PMC2597015 DOI: 10.1158/0008-5472.can-08-1771] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Early therapeutic efficacy of anti-death receptor 5 antibody (TRA-8) combined with gemcitabine was measured using diffusion-weighted magnetic resonance imaging (DWI) in an orthotopic pancreatic tumor model. Groups 1 to 4 of severe combined immunodeficient mice (n = 5-7 per group) bearing orthotopically implanted, luciferase-positive human pancreatic tumors (MIA PaCa-2) were subsequently (4-5 weeks thereafter) injected with saline (control), gemcitabine (120 mg/kg), TRA-8 (200 mug), or TRA-8 combined with gemcitabine, respectively, on day 0. DWI, anatomic magnetic resonance imaging, and bioluminescence imaging were done on days 0, 1, 2, and 3 after treatment. Three tumors from each group were collected randomly on day 3 after imaging, and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining was done to quantify apoptotic cellularity. At just 1 day after starting therapy, the changes of apparent diffusion coefficient (ADC) in tumor regions for group 3 (TRA-8) and group 4 (TRA-8/Gem) were 21 +/- 9% (mean +/- SE) and 27 +/- 3%, respectively, significantly higher (P < 0.05) than those of group 1 (-1 +/- 5%) and group 2 (-2 +/- 4%). There was no statistical difference in tumor volumes for the groups at this time. The mean ADC values of groups 2 to 4 gradually increased over 3 days, which were concurrent with tumor volume regressions and bioluminescence signal decreases. Apoptotic cell densities of tumors in groups 1 to 4 were 0.7 +/- 0.4%, 0.6 +/- 0.2%, 3.1 +/- 0.9%, and 4.7 +/- 1.0%, respectively, linearly proportional to the ADC changes on day 1. Further, the ADC changes were highly correlated with the previously reported mean survival times of animals treated with the same agents and doses. This study supports the clinical use of DWI for pancreatic tumor patients for early assessment of drug efficacy.
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Affiliation(s)
- Hyunki Kim
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Desiree E. Morgan
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Donald J. Buchsbaum
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Huadong Zeng
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - William E. Grizzle
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jason M. Warram
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Cecil R. Stockard
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Lacey R. McNally
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Joshua W. Long
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jeffrey C. Sellers
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Andres Forero
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Kurt R. Zinn
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
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Strimpakos A, Saif MW, Syrigos KN. Pancreatic cancer: from molecular pathogenesis to targeted therapy. Cancer Metastasis Rev 2008; 27:495-522. [PMID: 18427734 DOI: 10.1007/s10555-008-9134-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.
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Cooper WA, Kohonen-Corish MRJ, Zhuang L, McCaughan B, Kennedy C, Screaton G, Sutherland RL, Lee CS. Role and prognostic significance of tumor necrosis factor-related apoptosis-inducing ligand death receptor DR5 in nonsmall-cell lung cancer and precursor lesions. Cancer 2008; 113:135-42. [PMID: 18457325 DOI: 10.1002/cncr.23528] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor, DR5, mediates proapoptotic signals and is implicated in the pathogenesis of many neoplasms including nonsmall-cell lung cancer (NSCLC). METHODS In this study, immunohistochemical expression of DR5 was examined in 146 cases of stage I and II NSCLC as well as neoplastic precursor lesions and regional lymph node metastases using tissue microarrays. RESULTS High DR5 expression was observed in 67.1% of primary NSCLC, 55.6% of bronchial squamous carcinoma in situ, 40% of squamous metaplasia, as well as 76.5% of lymph node metastases. In all of these lesions, DR5 expression was significantly higher than in normal bronchial epithelium. Increased expression of DR5 correlated with poorly differentiated tumors and was inversely correlated with bronchioloalveolar carcinomas. There was no correlation with other clinicopathologic variables. A significant association was found between high DR5 expression and reduced overall survival in univariate analysis. Among smokers, high DR5 and tumor stage were independent predictors of reduced disease-free survival in multivariate analysis, however, DR5 was not an independent prognostic marker among the entire cohort of NSCLC. CONCLUSIONS These findings suggest that DR5 plays a role in the development of early-stage NSCLC and the high levels of DR5 expression suggest that these tumors may be susceptible to novel anticancer agents targeting the DR5 receptor and may improve patient survival, particularly for patients who are smokers.
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Affiliation(s)
- Wendy A Cooper
- Department of Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
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47
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Derosier LC, Vickers SM, Zinn KR, Huang Z, Wang W, Grizzle WE, Sellers J, Stockard CR, Zhou T, Oliver PG, Arnoletti P, Lobuglio AF, Buchsbaum DJ. TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth. Mol Cancer Ther 2008; 6:3198-207. [PMID: 18089714 DOI: 10.1158/1535-7163.mct-07-0299] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE To evaluate agonistic TRA-8 monoclonal antibody to human death receptor 5 (DR5) and gemcitabine in vitro and in an orthotopic pancreatic cancer model. EXPERIMENTAL DESIGN Pancreatic cancer cell lines were screened for DR5 expression, cytotoxicity, and apoptosis induced by TRA-8, gemcitabine, or gemcitabine and TRA-8. An orthotopic model of pancreatic cancer was established in severe combined immunodeficient mice. Mice were treated with TRA-8, gemcitabine, or a combination for one or two cycles of therapy. Tumor growth (ultrasound) and survival were analyzed. RESULTS All five pancreatic cancer cell lines showed DR5 protein expression and varying sensitivity to TRA-8-mediated cytotoxicity. MIA PaCa-2 cells were very sensitive to TRA-8, moderately resistant to gemcitabine, with additive cytotoxicity to the combination. S2-VP10 cells were resistant to TRA-8 and sensitive to gemcitabine with synergistic sensitivity to the combination. Combination treatment in vitro produced enhanced caspase-3 and caspase-8 activation. A single cycle of therapy produced comparable efficacy for single-agent TRA-8 and the combination of TRA-8 and gemcitabine, with significant reduction in tumor size and prolonged survival compared with gemcitabine alone or control animals. With two cycles of therapy, TRA-8 and combination therapy produced enhanced inhibition of tumor growth compared with single-agent gemcitabine or untreated animals. However, the combination regimen showed enhanced survival as compared with single-agent TRA-8. CONCLUSIONS Pancreatic cancer cell lines express varying levels of DR5 and differ in their sensitivity to TRA-8 and gemcitabine-induced cytotoxicity. TRA-8 with two cycles of gemcitabine therapy produced the best overall survival.
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Affiliation(s)
- Leo Christopher Derosier
- Departments of Surgery, University of Alabama at Birmingham, 1530 3rd Avenue South, Wallace Tumor Institute 674, Birmingham, AL 35294-6832, 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: 131] [Impact Index Per Article: 7.3] [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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Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. Oncogene 2007; 27:2055-63. [PMID: 17998943 DOI: 10.1038/sj.onc.1210840] [Citation(s) in RCA: 156] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising candidate for cancer therapy, however, emergence of drug resistance limits its potential use. Here, we report for the first time that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, sensitizes TRAIL-resistant LNCaP cells to TRAIL-mediated apoptosis through modulation of intrinsic and extrinsic apoptotic pathways. When combined with EGCG, Apo2L/TRAIL exhibited enhanced apoptotic activity in LNCaP cells characterized by three major molecular events. First, apoptosis induction was accompanied by the upregulation of poly(ADP-ribose) polymerase cleavage and modulation of pro- and antiapoptotic Bcl2 family of proteins. A synergistic inhibition of inhibitors of apoptosis with concomitant increase in caspase cleavage was observed. Second, pretreatment of cells with EGCG resulted in modulation of death-inducing signaling cascade complex involving DR4/TRAIL R1, Fas-associated death domain and FLICE-inhibitory protein proteins. Last, we observed a synergistic inhibition in the invasion and migration of LNCaP cells. This effect was observed to be mediated through inhibition in the protein expression of vascular endothelial growth factor, uPA and angiopoietin 1 and 2. Further, the activity and protein expression of MMP-2, -3 and -9 and upregulation of TIMP1 in cells treated with a combination of EGCG and TRAIL was observed. These data might have implications for developing new strategies aimed at eliminating prostate cancer cells resistant to TRAIL.
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DeRosier LC, Buchsbaum DJ, Oliver PG, Huang ZQ, Sellers JC, Grizzle WE, Wang W, Zhou T, Zinn KR, Long JW, Vickers SM. Combination treatment with TRA-8 anti death receptor 5 antibody and CPT-11 induces tumor regression in an orthotopic model of pancreatic cancer. Clin Cancer Res 2007; 13:5535s-5543s. [PMID: 17875786 PMCID: PMC3045836 DOI: 10.1158/1078-0432.ccr-07-1075] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
PURPOSE Evaluate the response of human pancreatic cancer cell lines and orthotopic tumors to TRA-8, an agonistic antibody to death receptor 5, in combination with irinotecan (CPT-11). EXPERIMENTAL DESIGN MIA PaCa-2 and S2VP10 cells were treated with TRA-8 and/or CPT 11. Cell viability was determined by ATP assay. JC-1 mitochondrial depolarization and Annexin V assays confirmed cell death by apoptosis. Immunoblotting was used to evaluate protein changes. MIA PaCa-2 cells were injected into the pancreas of severe combined immunodeficient mice. Mice underwent abdominal ultrasound to quantitate tumor size before and after treatment with twice weekly injections of 200 microg TRA-8 and/or 25 mg/kg CPT-11 for one or two treatment cycles, each lasting 2 weeks. RESULTS MIA PaCa-2 cells were more sensitive to TRA-8 and showed additive cytotoxicity, whereas S2VP10 cells showed synergistic cytotoxicity when treated with TRA-8 and CPT-11. Cell death occurred via apoptosis with increased cleavage of caspase-3, caspase-8, and caspase-9 and proapoptotic proteins Bid and poly(ADP)ribose polymerase after combination treatment compared with either agent alone. XIAP and Bcl-XL inhibitors of apoptosis were down-regulated. After a single cycle of in vivo combination therapy, tumor sizes had diminished significantly (P<0.001) at 8 days posttreatment compared with no treatment, CPT-11, and TRA-8; and there was a 50-day increase in survival with combination treatment over untreated controls (P=0.0002), 30 days over TRA-8, and a 36-day increase over CPT-11 monotherapy (P=0.0003). With two cycles of TRA-8/CPT-11 treatment, mean survival time increased significantly (P<0.001) to 169 days versus untreated controls, TRA-8 or CPT-11 (76, 121, or 108 days, respectively). CONCLUSIONS Combination TRA-8 and CPT-11 therapy produced enhanced cytotoxicity and survival in the MIA PaCa-2 orthotopic model of pancreatic cancer.
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Affiliation(s)
| | - Donald J. Buchsbaum
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Patsy G. Oliver
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Zhi-Qiang Huang
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jeffrey C. Sellers
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama
| | - William E. Grizzle
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Wenquan Wang
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Tong Zhou
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Kurt R. Zinn
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Joshua W. Long
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Selwyn M. Vickers
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
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