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1
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Wu Y, Millender J, Padgett B, Marx M, Madnick S, Puterbaugh R, Angelo KS, Hopkins CM, Morgan JR. An in vitro model to measure the strength and stiffness of the extracellular matrix synthesized de novo by human fibroblasts. IN VITRO MODELS 2025; 4:59-69. [PMID: 40160211 PMCID: PMC11950444 DOI: 10.1007/s44164-025-00081-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/06/2025] [Accepted: 01/06/2025] [Indexed: 04/02/2025]
Abstract
Purpose Alterations to the strength and stiffness of the human extracellular matrix (ECM) are the underlying pathology manifest in a wide range of diseases. These include inherited conditions, such as Ehlers Danlos syndrome, as well as acquired diseases such as fibrosis, which remains a major unmet medical need. To evaluate promising therapies, new models are needed that can measure the strength and stiffness of the human ECM. Methods Cultured human fibroblasts were seeded into circular troughs of agarose that had been molded into a 24 well plate and equilibrated with cell culture medium. The cells settled by gravity, aggregated and formed 3D ring-shaped tissues 5 mm in diameter without the aid of added exogenous scaffold material. The ECM proteins synthesized de novo by the rings were characterized by immuno-staining. The response of the rings to drug and growth factor treatments were assessed by measuring changes to the dimensions of the rings and by measuring levels of collagen. A tensile test was used to quantify drug and growth factor induced changes to the strength and stiffness of the rings. Results Ring-shaped tissues readily formed in the molds and synthesized de novo a circumferentially aligned collagen-rich fibrous ECM network positive for collagen type I, collagen type III and fibronectin. Low dose treatment with incyclinide, an inhibitor of matrix metalloproteinases (MMPs), increased strength and stiffness, whereas as a high dose decreased tensile properties, likely due to a toxic effect. Treatment with TGF-β1, a well-known driver of fibrosis, increased levels of collagen and tensile properties and mimicked the fibrotic environment in vitro. Treatment with PAT-1251, an inhibitor of the collagen crosslinking enzyme lysyl oxidase-like protein 2 (LOXL2), had no effect on levels of collagen but significantly reduced the strength and stiffness of the ring even when elevated by treatment with TGF-β1. Conclusion Human fibroblasts will self-assemble a 3D ring-shaped tissue and synthesize a fibrous network of ECM proteins whose tensile properties can be measured. The fibrotic environment can be mimicked by addition of TGF-β1, which increases levels of collagen as well as the strength and stiffness of the rings. Treatment with two drugs, incyclinide and PAT 1251 that were developed as potential treatments for diseases of the ECM, altered the strength and stiffness of the rings, thereby demonstrating the utility of the model for testing new therapies that target the biomechanics of the ECM. Supplementary Information The online version contains supplementary material available at 10.1007/s44164-025-00081-y.
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Affiliation(s)
- Yanying Wu
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Jayla Millender
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Becka Padgett
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Madeleine Marx
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Samantha Madnick
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Ryan Puterbaugh
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Katerina St. Angelo
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Caitlin M. Hopkins
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
| | - Jeffrey R. Morgan
- Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting St, Providence, G-B 393 USA
- Center for Alternatives to Animals in Testing, Brown University, Providence, RI USA
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2
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Memon AA, Vats S, Sundquist J, Li Y, Sundquist K. Mitochondrial DNA Copy Number: Linking Diabetes and Cancer. Antioxid Redox Signal 2022; 37:1168-1190. [PMID: 36169625 DOI: 10.1089/ars.2022.0100] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recent Advances: Various studies have suggested that mitochondrial DNA copy number (mtDNA-CN), a surrogate biomarker of mitochondrial dysfunction, is an easily quantifiable biomarker for chronic diseases, including diabetes and cancer. However, current knowledge is limited, and the results are controversial. This has been attributed mainly to methodology and study design. Critical Issues: The incidence of diabetes and cancer has increased significantly in recent years. Moreover, type 2 diabetes (T2D) has been shown to be a risk factor for cancer. mtDNA-CN has been associated with both T2D and cancer. However, it is not known whether mtDNA-CN plays any role in the association between T2D and cancer. Significance: In this review, we have discussed mtDNA-CN in diabetes and cancer, and reviewed the literature and methodology used in published studies so far. Based on the literature review, we have speculated how mtDNA-CN may act as a link between diabetes and cancer. Furthermore, we have provided some recommendations for reliable translation of mtDNA-CN as a biomarker. Future Directions: Further research is required to elucidate the role of mtDNA-CN in the association between T2D and cancer. If established, early lifestyle interventions, such as physical activity and diet control that improve mitochondrial function, may help preventing cancer in patients with T2D. Antioxid. Redox Signal. 37, 1168-1190.
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Affiliation(s)
- Ashfaque A Memon
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Sakshi Vats
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Yanni Li
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden
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3
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Baidya SK, Banerjee S, Adhikari N, Jha T. Selective Inhibitors of Medium-Size S1' Pocket Matrix Metalloproteinases: A Stepping Stone of Future Drug Discovery. J Med Chem 2022; 65:10709-10754. [PMID: 35969157 DOI: 10.1021/acs.jmedchem.1c01855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Among various matrix metalloproteinases (MMPs), MMPs having medium-size S1' pockets are established as promising biomolecular targets for executing crucial roles in cancer, cardiovascular diseases, and neurodegenerative diseases. However, no such MMP inhibitors (MMPIs) are available to date as drug candidates despite a lot of continuous research work for more than three decades. Due to a high degree of structural resemblance among these MMPs, designing selective MMPIs is quite challenging. However, the variability and uniqueness of the S1' pockets of these MMPs make them promising targets for designing selective MMPIs. In this perspective, the overall structural aspects of medium-size S1' pocket MMPs including the unique binding patterns of enzyme-inhibitor interactions have been discussed in detail to acquire knowledge regarding selective inhibitor designing. This overall knowledge will surely be a curtain raiser for the designing of selective MMPIs as drug candidates in the future.
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Affiliation(s)
- Sandip Kumar Baidya
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Suvankar Banerjee
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
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4
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Gunjur A, Balasubramanian A, Hafeez U, Menon S, Cher L, Parakh S, Gan HK. Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review. J Neurooncol 2022; 159:539-549. [PMID: 35933567 DOI: 10.1007/s11060-022-04092-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/06/2022] [Indexed: 10/15/2022]
Abstract
PURPOSE Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue. METHODS We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006-2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests. RESULTS A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0-33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models ('multiple models') had a significantly better median response rate than those tested using only one ('single model') or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027). CONCLUSION Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.
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Affiliation(s)
- Ashray Gunjur
- Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, UK.,Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia
| | - Adithya Balasubramanian
- Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia
| | - Umbreen Hafeez
- Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,Olivia Newton-John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,La Trobe University School of Cancer Medicine, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,Medical Student Education, University of Melbourne, Gratton St, Parkville, VIC, 3010, Australia
| | - Siddharth Menon
- Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,Olivia Newton-John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,La Trobe University School of Cancer Medicine, 145 Studley Road, Heidelberg, VIC, 3084, Australia
| | - Lawrence Cher
- Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia
| | - Sagun Parakh
- Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,Olivia Newton-John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, VIC, 3084, Australia.,La Trobe University School of Cancer Medicine, 145 Studley Road, Heidelberg, VIC, 3084, Australia
| | - Hui Kong Gan
- Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia. .,Olivia Newton-John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, VIC, 3084, Australia. .,La Trobe University School of Cancer Medicine, 145 Studley Road, Heidelberg, VIC, 3084, Australia. .,Department of Medicine, University of Melbourne, 145 Studley Road, Heidelberg, VIC, 3084, Australia.
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5
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Criscuolo D, Avolio R, Matassa DS, Esposito F. Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy. Front Oncol 2021; 11:797265. [PMID: 34888254 PMCID: PMC8650000 DOI: 10.3389/fonc.2021.797265] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/03/2021] [Indexed: 12/20/2022] Open
Abstract
Extensive metabolic remodeling is a fundamental feature of cancer cells. Although early reports attributed such remodeling to a loss of mitochondrial functions, it is now clear that mitochondria play central roles in cancer development and progression, from energy production to synthesis of macromolecules, from redox modulation to regulation of cell death. Biosynthetic pathways are also heavily affected by the metabolic rewiring, with protein synthesis dysregulation at the hearth of cellular transformation. Accumulating evidence in multiple organisms shows that the metabolic functions of mitochondria are tightly connected to protein synthesis, being assembly and activity of respiratory complexes highly dependent on de novo synthesis of their components. In turn, protein synthesis within the organelle is tightly connected with the cytosolic process. This implies an entire network of interactions and fine-tuned regulations that build up a completely under-estimated level of complexity. We are now only preliminarily beginning to reconstitute such regulatory level in human cells, and to perceive its role in diseases. Indeed, disruption or alterations of these connections trigger conditions of proteotoxic and energetic stress that could be potentially exploited for therapeutic purposes. In this review, we summarize the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, and their effects on the integrity of the mitochondrial proteome and functions. Finally, we highlight the potential held by this topic for future research directions and for the development of innovative therapeutic approaches.
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Affiliation(s)
- Daniela Criscuolo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Rosario Avolio
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Danilo Swann Matassa
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Franca Esposito
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
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6
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Habič A, Novak M, Majc B, Lah Turnšek T, Breznik B. Proteases Regulate Cancer Stem Cell Properties and Remodel Their Microenvironment. J Histochem Cytochem 2021; 69:775-794. [PMID: 34310223 DOI: 10.1369/00221554211035192] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Proteolytic activity is perturbed in tumors and their microenvironment, and proteases also affect cancer stem cells (CSCs). CSCs are the therapy-resistant subpopulation of cancer cells with tumor-initiating capacity that reside in specialized tumor microenvironment niches. In this review, we briefly summarize the significance of proteases in regulating CSC activities with a focus on brain tumor glioblastoma. A plethora of proteases and their inhibitors participate in CSC invasiveness and affect intercellular interactions, enhancing CSC immune, irradiation, and chemotherapy resilience. Apart from their role in degrading the extracellular matrix enabling CSC migration in and out of their niches, we review the ability of proteases to modulate CSC properties, which prevents their elimination. When designing protease-oriented therapies, the multifaceted roles of proteases should be thoroughly investigated.
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Affiliation(s)
- Anamarija Habič
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,The Jožef Stefan International Postgraduate School, Ljubljana, Slovenia
| | - Metka Novak
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Bernarda Majc
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,The Jožef Stefan International Postgraduate School, Ljubljana, Slovenia
| | - Tamara Lah Turnšek
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,The Jožef Stefan International Postgraduate School, Ljubljana, Slovenia.,Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
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7
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Waller V, Pruschy M. Combined Radiochemotherapy: Metalloproteinases Revisited. Front Oncol 2021; 11:676583. [PMID: 34055644 PMCID: PMC8155607 DOI: 10.3389/fonc.2021.676583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/21/2021] [Indexed: 12/25/2022] Open
Abstract
Besides cytotoxic DNA damage irradiation of tumor cells triggers multiple intra- and intercellular signaling processes, that are part of a multilayered, treatment-induced stress response at the unicellular and tumor pathophysiological level. These processes are intertwined with intrinsic and acquired resistance mechanisms to the toxic effects of ionizing radiation and thereby co-determine the tumor response to radiotherapy. Proteolysis of structural elements and bioactive signaling moieties represents a major class of posttranslational modifications regulating intra- and intercellular communication. Plasma membrane-located and secreted metalloproteinases comprise a family of metal-, usually zinc-, dependent endopeptidases and sheddases with a broad variety of substrates including components of the extracellular matrix, cyto- and chemokines, growth and pro-angiogenic factors. Thereby, metalloproteinases play an important role in matrix remodeling and auto- and paracrine intercellular communication regulating tumor growth, angiogenesis, immune cell infiltration, tumor cell dissemination, and subsequently the response to cancer treatment. While metalloproteinases have long been identified as promising target structures for anti-cancer agents, previous pharmaceutical approaches mostly failed due to unwanted side effects related to the structural similarities among the multiple family members. Nevertheless, targeting of metalloproteinases still represents an interesting rationale alone and in combination with other treatment modalities. Here, we will give an overview on the role of metalloproteinases in the irradiated tumor microenvironment and discuss the therapeutic potential of using more specific metalloproteinase inhibitors in combination with radiotherapy.
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Affiliation(s)
- Verena Waller
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Martin Pruschy
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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8
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D'Aguanno S, Mallone F, Marenco M, Del Bufalo D, Moramarco A. Hypoxia-dependent drivers of melanoma progression. J Exp Clin Cancer Res 2021; 40:159. [PMID: 33964953 PMCID: PMC8106186 DOI: 10.1186/s13046-021-01926-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
Hypoxia, a condition of low oxygen availability, is a hallmark of tumour microenvironment and promotes cancer progression and resistance to therapy. Many studies reported the essential role of hypoxia in regulating invasiveness, angiogenesis, vasculogenic mimicry and response to therapy in melanoma. Melanoma is an aggressive cancer originating from melanocytes located in the skin (cutaneous melanoma), in the uveal tract of the eye (uveal melanoma) or in mucosal membranes (mucosal melanoma). These three subtypes of melanoma represent distinct neoplasms in terms of biology, epidemiology, aetiology, molecular profile and clinical features.In this review, the latest progress in hypoxia-regulated pathways involved in the development and progression of all melanoma subtypes were discussed. We also summarized current knowledge on preclinical studies with drugs targeting Hypoxia-Inducible Factor-1, angiogenesis or vasculogenic mimicry. Finally, we described available evidence on clinical studies investigating the use of Hypoxia-Inducible Factor-1 inhibitors or antiangiogenic drugs, alone or in combination with other strategies, in metastatic and adjuvant settings of cutaneous, uveal and mucosal melanoma.Hypoxia-Inducible Factor-independent pathways have been also reported to regulate melanoma progression, but this issue is beyond the scope of this review.As evident from the numerous studies discussed in this review, the increasing knowledge of hypoxia-regulated pathways in melanoma progression and the promising results obtained from novel antiangiogenic therapies, could offer new perspectives in clinical practice in order to improve survival outcomes of melanoma patients.
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Affiliation(s)
- Simona D'Aguanno
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Fabiana Mallone
- Department of Sense Organs, Sapienza University of Rome, Rome, Italy
| | - Marco Marenco
- Department of Sense Organs, Sapienza University of Rome, Rome, Italy
| | - Donatella Del Bufalo
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
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9
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Singh A, Faccenda D, Campanella M. Pharmacological advances in mitochondrial therapy. EBioMedicine 2021; 65:103244. [PMID: 33647769 PMCID: PMC7920826 DOI: 10.1016/j.ebiom.2021.103244] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/21/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023] Open
Abstract
Mitochondria play a vital role in cellular metabolism and are central mediator of intracellular signalling, cell differentiation, morphogenesis and demise. An increasingly higher number of pathologies is linked with mitochondrial dysfunction, which can arise from either genetic defects affecting core mitochondrial components or malfunctioning pathways impairing mitochondrial homeostasis. As such, mitochondria are considered an important target in several pathologies spanning from neoplastic to neurodegenerative diseases as well as metabolic syndromes. In this review we provide an overview of the state-of-the-art in mitochondrial pharmacology, focusing on the novel compounds that have been generated in the bid to correct mitochondrial aberrations. Our work aims to serve the scientific community working on translational medical science by highlighting the most promising pharmacological approaches to target mitochondrial dysfunction in disease.
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Affiliation(s)
- Aarti Singh
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, 4 Royal College Street, NW1 0TU, London, United Kingdom
| | - Danilo Faccenda
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, 4 Royal College Street, NW1 0TU, London, United Kingdom
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, 4 Royal College Street, NW1 0TU, London, United Kingdom; Consortium for Mitochondrial Research (CfMR), University College London, Gower Street, WC1E 6BT, London, United Kingdom; Department of Biology, University of Rome TorVergata, Via della Ricerca Scientifica, Rome, 00133, Italy.
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10
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Krishnaswamy VR, Benbenishty A, Blinder P, Sagi I. Demystifying the extracellular matrix and its proteolytic remodeling in the brain: structural and functional insights. Cell Mol Life Sci 2019; 76:3229-3248. [PMID: 31197404 PMCID: PMC11105229 DOI: 10.1007/s00018-019-03182-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 05/29/2019] [Accepted: 05/31/2019] [Indexed: 12/29/2022]
Abstract
The extracellular matrix (ECM) plays diverse roles in several physiological and pathological conditions. In the brain, the ECM is unique both in its composition and in functions. Furthermore, almost all the cells in the central nervous system contribute to different aspects of this intricate structure. Brain ECM, enriched with proteoglycans and other small proteins, aggregate into distinct structures around neurons and oligodendrocytes. These special structures have cardinal functions in the normal functioning of the brain, such as learning, memory, and synapse regulation. In this review, we have compiled the current knowledge about the structure and function of important ECM molecules in the brain and their proteolytic remodeling by matrix metalloproteinases and other enzymes, highlighting the special structures they form. In particular, the proteoglycans in brain ECM, which are essential for several vital functions, are emphasized in detail.
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Affiliation(s)
| | - Amit Benbenishty
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Pablo Blinder
- Neurobiology, Biochemistry and Biophysics School, Tel Aviv University, Tel Aviv, Israel
- Sagol School for Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
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11
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Protasoni M, Kroon AM, Taanman JW. Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL-3. Oncotarget 2018; 9:33818-33831. [PMID: 30333912 PMCID: PMC6173462 DOI: 10.18632/oncotarget.26107] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 08/24/2018] [Indexed: 01/23/2023] Open
Abstract
Tetracyclines have anticancer properties in addition to their well-known antibacterial properties. It has been proposed that tetracyclines slow metastasis and angiogenesis through inhibition of matrix metalloproteinases. However, we believe that the anticancer effect of tetracyclines is due to their inhibition of mitochondrial protein synthesis, resulting in a decrease of the mitochondrial energy generating capacity. Several groups have developed analogs that are void of antibacterial action. An example is COL-3, which is currently tested for its anticancer effects in clinical trials. We have undertaken a comparative study of the tetracycline analogs COL-3 and doxycycline, which has an antibacterial function, to further investigate the role of the mitochondrial energy generating capacity in the anticancer mechanism and, thereby, evaluate the usefulness of mitochondria as an oncotarget. Our experiments with cultures of the human A549, COLO357 and HT29 cancer cells and fibroblasts indicated that COL-3 is significantly more cytotoxic than doxycycline. Mitochondrial translation assays demonstrated that COL-3 has retained its inhibitory effect on mitochondrial protein synthesis. Both drugs caused a severe decrease in the levels of mitochondrially encoded cytochrome-c oxidase subunits and cytochrome-c oxidase activity. In addition, COL-3 produced a marked drop in the level of nuclear-encoded succinate dehydrogenase subunit A and citrate synthase activity, indicating that COL-3 has multiple inhibitory effects. Contrary to COL-3, the anticancer action of doxycycline appears to be based specifically on inhibition of mitochondrial protein synthesis, which is thought to affect rapidly proliferating cancer cells more than healthy tissue. Doxycycline is likely to cause less side effects that COL-3.
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Affiliation(s)
- Margherita Protasoni
- Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK
| | - Albert M Kroon
- Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK
| | - Jan-Willem Taanman
- Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK
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12
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Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers. J Cereb Blood Flow Metab 2016; 36:1481-507. [PMID: 27323783 PMCID: PMC5012524 DOI: 10.1177/0271678x16655551] [Citation(s) in RCA: 464] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/26/2016] [Indexed: 02/01/2023]
Abstract
Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood-brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.
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Affiliation(s)
- Ralf G Rempe
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - Anika M S Hartz
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Björn Bauer
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
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Abstract
Chemically modified tetracycline 3 (CMT-3) is a potential anticancer drug because of its retained matrix metalloproteinases inhibitory property. In the present study,we showed that CMT-3 significantly inhibited the growth and proliferation of human hepatocellular carcinoma HepG2 cells. Novel mechanisms including increased intracellular autophagy level and high-mobility group box 1 (HMGB1)release were involved. In addition, a major Danshen ingredient, tanshinone IIA sodium sulfonate (TSN-SS),significantly increased the cytotoxic effects of CMT-3 in HepG2 cells. Combining CMT-3 with TSN-SS led to enhanced accumulation of endogenous LC3-II, but reduced HMGB1 cytoplasmic translocation. Altogether, these findings suggest that autophagy and HMGB1 release may play important roles in the anticancer effect of CMT-3. As an ovel candidate for cancer therapy, CMT-3 may be used in combination with TSN-SS, which possibly facilitates the execution of a death signal (e.g. autophagy) and prevents the survival of an inducer (e.g. HMGB1 cytoplasmic translocation), thus improving its therapeutic effect.
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Gounder MM, Nayak L, Sahebjam S, Muzikansky A, Sanchez AJ, Desideri S, Ye X, Ivy SP, Nabors LB, Prados M, Grossman S, DeAngelis LM, Wen PY. Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors. J Clin Oncol 2015; 33:3186-92. [PMID: 26282642 DOI: 10.1200/jco.2015.61.1525] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
PURPOSE Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations. PATIENT AND METHODS Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival. RESULTS Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n=5) and cytotoxic (n=3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, <one to 56 cycles), and 96% were evaluable for primary end points. During cycle 1, grade≥3 nonhematologic and grade≥4 hematologic toxicities were 5% (28 of 565 adverse events) and 0.9% (five of 565 adverse events), respectively, and 66% of these occurred at the highest dose level. There was one death attributed to drug. Overall response rate (complete and partial response) was 5.5%. Median progression-free and overall survival times were 1.8 and 6 months, respectively. CONCLUSION Patients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties in this population.
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Affiliation(s)
- Mrinal M Gounder
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
| | - Lakshmi Nayak
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Solmaz Sahebjam
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Alona Muzikansky
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Armando J Sanchez
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Serena Desideri
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Xiaobu Ye
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - S Percy Ivy
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - L Burt Nabors
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Michael Prados
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Stuart Grossman
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Lisa M DeAngelis
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Patrick Y Wen
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
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15
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The role of targeted therapies in the management of progressive glioblastoma. J Neurooncol 2014; 118:557-99. [DOI: 10.1007/s11060-013-1339-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Accepted: 12/28/2013] [Indexed: 12/28/2022]
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Potential clinical applications of matrix metalloproteinase inhibitors and their future prospects. Int J Biol Markers 2013; 28:117-30. [PMID: 23787494 DOI: 10.5301/jbm.5000026] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2013] [Indexed: 12/28/2022]
Abstract
Matrix metalloproteinases (MMPs) are endopeptidases that are involved in extracellular matrix degradation. They are also implicated in a number of abnormal bioprocesses, such as tumor growth, invasion, and metastasis. Therefore, controlling MMP activities has generated considerable interest as a possible therapeutic target. The tissue inhibitors of metalloproteinases (TIMPs) are the major naturally occurring proteins that specifically inhibit MMPs and assist in maintaining the balance between extracellular matrix destruction and formation. However, TIMPs are probably not suitable for pharmacological applications due to their short half-lives in vivo. During the last few decades, synthetic MMP inhibitors (MMPIs) have undergone rapid clinical development in attempts to control MMP enzymatic activities in abnormal bioprocesses. Although studies with these agents have met with limited clinical success, the field of MMPIs is still expanding, and generation of highly effective and selective MMPIs might be a promising direction of this research area.
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Hagemann C, Anacker J, Ernestus RI, Vince GH. A complete compilation of matrix metalloproteinase expression in human malignant gliomas. World J Clin Oncol 2012; 3:67-79. [PMID: 22582165 PMCID: PMC3349915 DOI: 10.5306/wjco.v3.i5.67] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 11/12/2011] [Accepted: 04/24/2012] [Indexed: 02/06/2023] Open
Abstract
Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases (MMPs) were found in glioblastoma (GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma (LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory data available. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy.
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Affiliation(s)
- Carsten Hagemann
- Carsten Hagemann, Ralf-Ingo Ernestus, Giles H Vince, Department of Neurosurgery, Tumorbiology Laboratory, University of Würzburg, Josef-Schneider-Str. 11, D-97080 Würzburg, Germany
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