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Mayasin YP, Osinnikova MN, Kharisova CB, Kitaeva KV, Filin IY, Gorodilova AV, Kutovoi GI, Solovyeva VV, Golubev AI, Rizvanov AA. Extracellular Matrix as a Target in Melanoma Therapy: From Hypothesis to Clinical Trials. Cells 2024; 13:1917. [PMID: 39594665 PMCID: PMC11592585 DOI: 10.3390/cells13221917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell-ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, may inhibit tumor progression and enhance the efficacy of combination treatment with immune checkpoint inhibitors (ICIs), chemotherapy, or immunotherapy. In this review, we combine the results of different approaches targeting extracellular matrix elements in melanoma in preclinical and clinical studies. The identified limitations of many approaches, including side effects, low selectivity, and toxicity, indicate the need for further studies to optimize therapy. Nevertheless, significant progress in expanding our understanding of tumor biology and the development of targeted therapies holds great promise for the early approaches developed several decades ago to inhibit metastasis through ECM targeting.
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Affiliation(s)
- Yuriy P. Mayasin
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Maria N. Osinnikova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Chulpan B. Kharisova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Kristina V. Kitaeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Ivan Y. Filin
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Anna V. Gorodilova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Grigorii I. Kutovoi
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Valeriya V. Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Anatolii I. Golubev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
| | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (Y.P.M.); (M.N.O.); (C.B.K.); (K.V.K.); (I.Y.F.); (A.V.G.); (G.I.K.); (V.V.S.); (A.I.G.)
- Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, 420111 Kazan, Russia
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Characterization of Active MMP9 in Chronic Inflammatory Diseases Using a Novel Anti-MMP9 Antibody. Antibodies (Basel) 2023; 12:antib12010009. [PMID: 36810514 PMCID: PMC9944116 DOI: 10.3390/antib12010009] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/31/2022] [Accepted: 01/12/2023] [Indexed: 01/21/2023] Open
Abstract
Matrix metalloproteinase 9 (MMP9), a protease implicated in multiple diseases, is secreted as an inactive zymogen and requires proteolytic removal of the pro-domain for activation. The relative levels and functionality of the pro- and active-MMP9 isoforms in tissues are not characterized. We generated a specific antibody that distinguishes an active form of MMP9, F107-MMP9, from the inactive pro-MMP9 isoform. Using multiple in vitro assays and specimen types, we show that F107-MMP9 expression is localized and disease-specific compared with its more abundant parental pro-form. It is detected around sites of active tissue remodeling, including fistulae of inflammatory bowel and dermal fissures in hidradenitis suppurativa, and is expressed by myeloid cells, including macrophages and neutrophils. Together, our findings provide insights into the distribution and potential role of MMP9 in inflammatory diseases.
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Patel EN, Turner LD, Hixon MS, Janda KD. Identification of Slow-Binding Inhibitors of the BoNT/A Protease. ACS Med Chem Lett 2022; 13:742-747. [PMID: 35450355 PMCID: PMC9014515 DOI: 10.1021/acsmedchemlett.2c00028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/04/2022] [Indexed: 12/20/2022] Open
Abstract
Botulinum neurotoxin A (BoNT/A) is a lethal toxin, which causes botulism, and is categorized as a bioterrorism threat, which causes flaccid paralysis and death. Botulinum A neurotoxicity is governed through its light chain (LC), a zinc metalloprotease. Pharmacological investigations aimed at negating BoNT/A's LC have typically looked to inhibitors that have been shown to inhibit the light chain's activity by reversible zinc chelation within its active site. This report outlines the first examples of nonpeptidic inhibitors of the BoNT/A LC that possess slow-binding kinetics, a needed logic to counteract the longevity of BoNT/A. Cyclopropane, alkyl, and alkenyl derivatives of 2,4-dichlorocinamic hydroxamic acid (DCHA) were shown to possess both one-step and two-step slow-binding kinetics. Structure-kinetic relationships (SKRs) were observed and were rationalized with the aid of docking models that predicted improved interactions with residues within a hydrophobic cleft adjacent to the active site.
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Affiliation(s)
- Ealin N. Patel
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Lewis D. Turner
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
- Biosplice Therapeutics, 9360 Towne Centre Drive, San Diego, California 92121, United States
| | - Mark S. Hixon
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Kim D. Janda
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
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Augoff K, Hryniewicz-Jankowska A, Tabola R, Stach K. MMP9: A Tough Target for Targeted Therapy for Cancer. Cancers (Basel) 2022; 14:cancers14071847. [PMID: 35406619 PMCID: PMC8998077 DOI: 10.3390/cancers14071847] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/27/2022] [Accepted: 03/31/2022] [Indexed: 02/01/2023] Open
Abstract
Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.
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Affiliation(s)
- Katarzyna Augoff
- Department of Surgical Education, Wroclaw Medical University, 50-367 Wroclaw, Poland
- Department of Chemistry and Immunochemistry, Wroclaw Medical University, 50-367 Wroclaw, Poland;
- Correspondence:
| | | | - Renata Tabola
- Department of Thoracic Surgery, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Kamilla Stach
- Department of Chemistry and Immunochemistry, Wroclaw Medical University, 50-367 Wroclaw, Poland;
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Das S, Amin SA, Gayen S, Jha T. Insight into the structural requirements of gelatinases (MMP-2 and MMP-9) inhibitors by multiple validated molecular modelling approaches: Part II. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2022; 33:167-192. [PMID: 35301933 DOI: 10.1080/1062936x.2022.2041722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/03/2022] [Indexed: 06/14/2023]
Abstract
Inhibition of the matrix metalloproteinases (MMPs) is effective against metastasis of secondary tumours. Previous MMP inhibitors have failed in clinical trials due to their off-target toxicity in solid tumours. Thus, newer MMP inhibitors now have paramount importance. Here, different molecular modelling techniques were applied on a dataset of 110 gelatinase (MMP-2 and MMP-9) inhibitors. The objectives of the present study were to identify structural fingerprints for gelatinase inhibition and also to develop statistically validated QSAR models for the screening and prediction of different derivatives as MMP-2 (gelatinase A) and MMP-9 (gelatinase B) inhibitors. The Bayesian classification study provided the ROC values for the training set of 0.837 and 0.815 for MMP-2 and MMP-9, respectively. The linear model also produced the leave-one-out cross-validated Q2 of 0.805 (eq. 1, MMP-2) and 0.724 (eq. 2, MMP-9), an r2 of 0.845 (eq. 1, MMP-2) and 0.782 (eq. 2, MMP-9), an r2Pred of 0.806 (eq. 1, MMP-2) and 0.732 (eq. 2, MMP-9). Similarly, non-linear learning models were also statistically significant and reliable. Overall, this study may help in the rational design of newer compounds with higher gelatinase inhibition to fight against both primary and secondary cancers in future.
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Affiliation(s)
- S Das
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - S A Amin
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - S Gayen
- Laboratory of Drug Design and Discovery, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - T Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
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Das S, Amin SA, Jha T. Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies. Eur J Med Chem 2021; 223:113623. [PMID: 34157437 DOI: 10.1016/j.ejmech.2021.113623] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/18/2021] [Accepted: 06/03/2021] [Indexed: 12/30/2022]
Abstract
Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are collectively known as gelatinases whereas MMP-2 is gelatinase-A and MMP-9 is termed as gelatinase-B. Gelatinases and other matrix metalloproteinases (MMPs) have long been associated with solid tumor invasion, metastasis and angiogenesis. However, there is paucity of data available regarding the role of gelatinases in hematological malignancies. Recent studies have shown that gelatinases activities or functions are correlated with hematological malignancies. Strategies for designing more specific gelatinase inhibitors like catalytic (CAT) domain inhibitors and hemopexin (PEX) domain inhibitors as well as signaling pathway based or gelatinase expression inhibitors had been reported against hematologic malignant cells. Several substrate based non-selective to non-substrate based relatively selective synthetic matrix metalloproteinase inhibitors (MMPIs) had been developed. Few MMPIs had reached in clinical trials during the period of 1990s-2000s. Unfortunately the anti-tumor and anti-metastatic efficacies of these MMPIs were not justified with patients having several advanced stage solid tumor cancers in any substantial number of clinical trials. Till date not a single MMPI passed phase III clinical trials designed for advanced metastatic cancers due to adverse events as well as lack of ability to show uniformity in disease prolongation. With the best of our knowledge no clinical trial study has been reported with small molecule synthetic inhibitors against hematological malignancies. This review looks at the outcome of clinical trials of MMPIs for advanced stage solid tumors. This can therefore, act as a learning experience for future development of successful gelatinase inhibitors for the management of hematological malignancies.
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Affiliation(s)
- Sanjib Das
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
| | - Sk Abdul Amin
- 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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Gabriel CER, Nguyen TT, Gargano EM, Fisher JF, Chang M, Mobashery S. Metabolism of the Selective Matrix Metalloproteinase-9 Inhibitor ( R)-ND-336. ACS Pharmacol Transl Sci 2021; 4:1204-1213. [PMID: 34151210 DOI: 10.1021/acsptsci.1c00063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Indexed: 01/02/2023]
Abstract
(R)-ND-336-designated as compound (R)-5-is a highly selective inhibitor of matrix metalloproteinase (MMP)-9 with efficacy in accelerating diabetic wound healing in murine models. (R)-ND-336 belongs to the class of thiirane inhibitors of MMPs and it is currently undergoing Investigation New Drug (IND)-enabling studies. We investigated the in vitro metabolism of (R)-ND-336 using S9 fractions obtained from mice, rats, dogs, minipigs, monkeys, and humans in order to select the rodent and nonrodent species for toxicology studies. Three metabolites were observed. One metabolite, M3, was observed across all species. Metabolite M2 was found in rats, monkeys, and humans. Metabolite M1 was observed only in rats. The identities of the metabolites were suggested by liquid chromatography/tandem mass spectroscopy (LC/MS-MS) analyses, which were authenticated by comparison to synthetic samples. Metabolites M2 and M3 arise from oxidative deamination of (R)-ND-336 by monoamine oxidase to give the arylaldehyde as a transient (and unobserved) intermediate. Reductive metabolism of this aldehyde gives the alcohol metabolite M2, while further oxidative metabolism of the aldehyde produces the carboxylate metabolite M3. A minor route of metabolism, seen only in rats, is N-acetylation of (R)-ND-336 to give the acetamide M1. The metabolism of (R)-ND-336 is distinctly different from that of the prototype member of this thiirane class ((±)-1, lacking the 4-aminomethyl aryl substituent) which is metabolized primarily by oxidation α to the sulfone to lead to a benzenesulfinate metabolite. All three metabolites are poorer MMP-9 inhibitors, compared to (R)-ND-336 (MMP-9, K i = 19 nM): M3, MMP-9 IC50 > 100 μM; M2, K i = 390 nM; and M1, IC50 > 100 μM). The rat and the minipig were selected as the rodent and nonrodent species, respectively, for toxicology studies.
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Affiliation(s)
- Charles Edwin Raja Gabriel
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Trung T Nguyen
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Emanuele Marco Gargano
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Jed F Fisher
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Mayland Chang
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
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Song R, Qiao W, He J, Huang J, Luo Y, Yang T. Proteases and Their Modulators in Cancer Therapy: Challenges and Opportunities. J Med Chem 2021; 64:2851-2877. [PMID: 33656892 DOI: 10.1021/acs.jmedchem.0c01640] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Proteostasis is the process of regulating intracellular proteins to maintain the balance of the cell proteome, which is crucial for cancer cell survival. Several proteases located in the cytoplasm, mitochondria, lysosome, and extracellular environment have been identified as potential antitumor targets because of their involvement in proteostasis. Although the discovery of small-molecule inhibitors targeting proteases faces particular challenges, rapid advances in chemical biology and structural biology, and the new technology of drug discovery have facilitated the development of promising protease modulators. In this review, the protein structure and function of important tumor-related proteases and their inhibitors are presented. We also provide a prospective on advances and the outlook of new drug strategies that target these proteases.
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Affiliation(s)
- Rao Song
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenliang Qiao
- Lung Cancer Center, Laboratory of Lung Cancer, West China Medical School, Sichuan University, Chengdu 610041, China
| | - Jun He
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiasheng Huang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Youfu Luo
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.,Laboratory of Human Disease and Immunotherapies, West China Hospital, Sichuan University, Chengdu 610041, China
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Xu T, Xu X, Liu PC, Mao H, Ju S. Transcriptomic Analyses and Potential Therapeutic Targets of Pancreatic Cancer With Concomitant Diabetes. Front Oncol 2020; 10:563527. [PMID: 33251135 PMCID: PMC7672183 DOI: 10.3389/fonc.2020.563527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/13/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) known as non-insulin-dependent diabetes mellitus, which is increasingly acknowledged as being associated with an increased risk for a series of cancers. Pancreatic cancer is currently the fourth most common cause of cancer-related mortality, which has been proved to be worsened by internal diabetic condition. However, the underlying molecular mechanisms are less addressed. Furthermore, current knowledge revealed that therapeutic strategy by anti-diabetes for pancreatic cancer under diabetes condition have no satisfactory efficacy, and nor by chemotherapy in our study. METHODS To clarify these mysteries and widen our knowledge, both obesity-associated and non-obese-associated T2DM mouse models were generated by chemical induction with streptozotocin (STZ) and leptin receptor knockout (db/db) in mice. Then, the process of tumor progression was researched, and the gene expression profiling of pancreatic cancer in mice was performed using RNA-seq. RESULTS Our results showed that pancreatic cancer malignancy was increased with notable proliferation and metastatic potential in two diabetic mice model. Totally, 136 and 64 significantly differentially expressed genes (DEGs) were identified in STZ and db/db mice by transcriptomic analysis. The results also suggested that different carcinogenesis-related genes and potential molecular mechanisms contribute to the malignancy of pancreatic cancer in obesity-associated and non-obesity-associated T2DM. In obesity-associated db/db mice, the GO subcategories associated with most of the genes with downregulated expression are involved in the immune response. However, in non-obesity-associated STZ mice, in addition to the immune response category, the enriched subcategories also included angiogenesis and the extracellular matrix. While, two genes respectively encoding MMP-2 and MMP-9 were simultaneously abnormal up-regulated in pancreatic cancer tissue from diabetic mice of both STZ and db/db, that could act as potential therapeutic targets for significantly suppressing the malignant progression. Furthermore, an optimizing therapeutic strategy was further proposed that combining MMP-2/9 inhibitor with gemcitabine significantly enhanced anti-tumor effects on pancreatic cancer under diabetic condition, providing a theoretical basis for clinical applications. CONCLUSIONS Generally, this study provides a comprehensive insight into diabetes as a risk factor for pancreatic cancer and has the potential to guide the development of enhanced treatment strategies.
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Affiliation(s)
- Tingting Xu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Xiaoxuan Xu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Peng-Cheng Liu
- The College of Life Science, Anhui Normal University, Wuhu, China
| | - Hui Mao
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, United States
| | - Shenghong Ju
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
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Ye Y, Kuang X, Xie Z, Liang L, Zhang Z, Zhang Y, Ma F, Gao Q, Chang R, Lee HH, Zhao S, Su J, Li H, Peng J, Chen H, Yin M, Peng C, Yang N, Wang J, Liu J, Liu H, Han L, Chen X. Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1. Genome Med 2020; 12:83. [PMID: 32988398 PMCID: PMC7523356 DOI: 10.1186/s13073-020-00780-z] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 09/10/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Immune checkpoint blockade (ICB) therapy has demonstrated considerable clinical benefit in several malignancies, but has shown favorable response in only a small proportion of cancer patients. Recent studies have shown that matrix metalloproteinases (MMPs) are highly associated with the microenvironment of tumors and immune cells. However, it is unknown whether MMPs are involved in immunotherapy. METHODS Here, we used integrative analysis to explore the expression landscape of the MMP family and its association with immune features across multiple cancer types. We used T cell cytotoxicity-mediated tumor killing assay to determine the co-cultured T cell activity of SB-3CT, an MMP2/9 inhibitor. We then used in vitro assays to examine the regulating roles of SB-3CT on PD-L1. We further characterized the efficacy of SB-3CT, in combination with anti-PD-1 and/or anti-CTLA4 treatment in mouse models with melanoma and lung cancer. RESULTS Our computational analysis demonstrated a strong association between MMP2/9 and immune features. We demonstrated that inhibition of MMP2/9 by SB-3CT significantly reduced the tumor burden and improved survival time by promoting anti-tumor immunity. Mechanistically, we showed that SB-3CT treatment significantly diminished both mRNA and protein levels of PD-L1 in cancer cells. Pre-clinically, SB-3CT treatment enhanced the therapeutic efficacy of PD-1 or CTLA-4 blockade in the treatment of both primary and metastatic tumors. CONCLUSIONS Our study unraveled novel molecular mechanisms regarding the regulation of tumor PD-L1 and provided a novel combination therapeutic strategy of SB-3CT and ICB therapy to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Youqiong Ye
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA.
| | - Xinwei Kuang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Zuozhong Xie
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Long Liang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Medical Genetics & School of Life Sciences, Central South University, Changsha, 410008, Hunan, China
| | - Zhao Zhang
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA
| | - Yongchang Zhang
- Department of medical oncology, lung cancer and gastrointestinal unit, Hunan cancer hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China
| | - Fangyu Ma
- Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Qian Gao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Ruimin Chang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Heng-Huan Lee
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Shuang Zhao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Hui Li
- Medical Genetics & School of Life Sciences, Central South University, Changsha, 410008, Hunan, China
| | - Jingbo Peng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Huifang Chen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Minzhu Yin
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China
| | - Nong Yang
- Department of medical oncology, lung cancer and gastrointestinal unit, Hunan cancer hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China
| | - Jing Wang
- Early Clinical Trial Center, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China
| | - Jing Liu
- Medical Genetics & School of Life Sciences, Central South University, Changsha, 410008, Hunan, China
| | - Hong Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China.
- Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Leng Han
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410013, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.
- Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, 410008, Hunan, China.
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11
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Ulrich CC, Arinze V, Wandscheer CB, Copley Salem C, Nabati C, Etezadi-Amoli N, Burkin HR. Matrix metalloproteinases 2 and 9 are elevated in human preterm laboring uterine myometrium and exacerbate uterine contractility†. Biol Reprod 2020; 100:1597-1604. [PMID: 30951583 DOI: 10.1093/biolre/ioz054] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 02/15/2019] [Accepted: 04/03/2019] [Indexed: 12/14/2022] Open
Abstract
Matrix metalloproteinases 2 and 9 (MMP2/9) have previously been shown to be elevated in serum and amniotic fluid from women undergoing preterm birth. We performed experiments to determine the effects of MMP2/9 on uterine contraction and birth timing. Pregnant mice were injected daily with 50 mg/kg of SB-3CT or vehicle control beginning on gestational day 14-18 to determine if MMP2/9 inhibition would affect parturition timing. MMP2/9 expression in human myometrial tissue was determined by Simple Western (Wes) and semiquantitative western blot. Purified MMP2/9 and SB-3CT inhibitor were added to human myometrial strips to determine the effects of MMP2/9 on oxytocin-induced uterine contraction. Parturition was delayed in mice treated with MMP2/9 inhibitor SB-3CT. MMP2/9 protein levels were elevated in preterm laboring uterine myometrium. Gelatinase activity was confirmed in cell extracts and supernatants from immortalized and primary human uterine myometrial cells in culture. Addition of purified MMP2/9 increased the oxytocin-induced contractile response in myometrial tissue strips from pregnant women. In contrast, addition of the MMP2/9 inhibitor SB-3CT decreased the contractile response to oxytocin in a dose-dependent manner. These results suggest abnormal MMP2/9 expression affects the contractile state of the uterine myometrium to promote parturition and that MMP2/9 inhibition attenuates this effect.
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Affiliation(s)
- Craig C Ulrich
- University of Nevada, Reno School of Medicine, Department of Pharmacology, Reno, Nevada, USA
| | - Veronica Arinze
- University of Nevada, Reno School of Medicine, Department of Pharmacology, Reno, Nevada, USA
| | | | - Christian Copley Salem
- University of Nevada, Reno School of Medicine, Department of Pharmacology, Reno, Nevada, USA
| | - Camellia Nabati
- University of Nevada, Reno School of Medicine, Department of Pharmacology, Reno, Nevada, USA
| | - Neda Etezadi-Amoli
- University of Nevada, Reno School of Medicine, Department of Obstetrics and Gynecology, Reno, Nevada, USA
| | - Heather R Burkin
- University of Nevada, Reno School of Medicine, Department of Pharmacology, Reno, Nevada, USA
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12
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Yang S, Wang L, Pan W, Bayer W, Thoens C, Heim K, Dittmer U, Timm J, Wang Q, Yu Q, Luo J, Liu Y, Hofmann M, Thimme R, Zhang X, Chen H, Wang H, Feng X, Yang X, Lu Y, Lu M, Yang D, Liu J. MMP2/MMP9-mediated CD100 shedding is crucial for inducing intrahepatic anti-HBV CD8 T cell responses and HBV clearance. J Hepatol 2019; 71:685-698. [PMID: 31173811 DOI: 10.1016/j.jhep.2019.05.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 04/30/2019] [Accepted: 05/14/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS CD100 is constitutively expressed on T cells and can be cleaved from the cell surface by matrix metalloproteases (MMPs) to become soluble CD100 (sCD100). Both membrane-bound CD100 (mCD100) and sCD100 have important immune regulatory functions that promote immune cell activation and responses. This study investigated the expression and role of mCD100 and sCD100 in regulating antiviral immune responses during HBV infection. METHODS mCD100 expression on T cells, sCD100 levels in the serum, and MMP expression in the liver and serum were analysed in patients with chronic HBV (CHB) and in HBV-replicating mice. The ability of sCD100 to mediate antigen-presenting cell maturation, HBV-specific T cell activation, and HBV clearance were analysed in HBV-replicating mice and patients with CHB. RESULTS Patients with CHB had higher mCD100 expression on T cells and lower serum sCD100 levels compared with healthy controls. Therapeutic sCD100 treatment resulted in the activation of DCs and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell responses, and accelerated HBV clearance, whereas blockade of its receptor CD72 attenuated the intrahepatic anti-HBV CD8 T cell response. Together with MMP9, MMP2 mediated mCD100 shedding from the T cell surface. Patients with CHB had significantly lower serum MMP2 levels, which positively correlated with serum sCD100 levels, compared with healthy controls. Inhibition of MMP2/9 activity resulted in an attenuated anti-HBV T cell response and delayed HBV clearance in mice. CONCLUSIONS MMP2/9-mediated sCD100 release has an important role in regulating intrahepatic anti-HBV CD8 T cell responses, thus mediating subsequent viral clearance during HBV infection. LAY SUMMARY Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. The clearance of HBV relies largely on an effective T cell immune response, which usually becomes dysregulated in chronic HBV infection. Our study provides a new mechanism to elucidate HBV persistence and a new target for developing immunotherapy strategies in patients chronically infected with HBV.
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Affiliation(s)
- Shangqing Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lu Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wen Pan
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wibke Bayer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany
| | - Christine Thoens
- Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf 40225, Germany
| | - Kathrin Heim
- Department of Medicine II, University Hospital Freiburg, Freiburg 79110, Germany; Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany
| | - Joerg Timm
- Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf 40225, Germany
| | - Qin Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qing Yu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jinzhuo Luo
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yanan Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Maike Hofmann
- Department of Medicine II, University Hospital Freiburg, Freiburg 79110, Germany; Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg, Freiburg 79110, Germany; Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany
| | - Xiaoyong Zhang
- Hepatology Unit and Key Laboratory for Organ Failure Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510551, China
| | - Hongtao Chen
- Department of Infectious Diseases, The Second Clinical Medical College, Jinan University, Shenzhen 510632, China
| | - Hua Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yinping Lu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen 45147, Germany
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Xu T, Chang D, Cai Y, Min S, Ma Y, Mao H, Ju S. Targeting of an antecedent proteinase by an activatable probe with deep tissue penetration facilitates early visualization and dynamic malignancy evaluation of orthotopic pancreatic ductal adenocarcinoma (PDAC). Biomater Sci 2019; 7:3320-3333. [PMID: 31210201 DOI: 10.1039/c9bm00441f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and most commonly diagnosed at an advanced stage; therefore, early detection with an effective approach is vital. However, due to the anatomical stealthiness and hypovascular features of PDAC, clinically available imaging techniques lack specificity and sensitivity for early detection. As important components of the tumour microenvironment, elevated matrix metalloproteinase (MMP) levels during the early stages of tumour formation lead to tumour invasion and metastases by degrading the extracellular matrix. Thus, in the current study, we hypothesized that MMPs might be promising markers for early visualization and prognosis evaluation of PDAC. An MMP activatable probe, I780BP-PEG12, was synthesized utilizing a long wavelength near-infrared (NIR) fluorophore that could map the dynamic development of orthotopic PDAC in vivo with deep tissue penetration. Elevated MMP activity in tumours was detected as early as 4 days after tumour transplantation. At that time, the tumour diameter was approximately 3 mm, which is much smaller than the size visualized by clinical approaches. Furthermore, much higher levels of MMP activity were detected in PDAC under diabetic conditions, which promote the malignant actions of tumours. By noninvasively monitoring MMP alteration, tumour growth, and prognostic evaluation, we found that malignant actions under diabetic conditions were reversed by inhibition of MMPs. Generally, in addition to earlier visualization of PDAC, a probe targeting MMPs can facilitate dynamic monitoring of tumour progression and inhibitory treatment in vivo, which is beneficial for personal therapeutic strategy planning and optimization of PDAC management, especially for diabetic individuals.
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Affiliation(s)
- Tingting Xu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
| | - Di Chang
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
| | - Yu Cai
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
| | - Shudan Min
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
| | - Yuanyuan Ma
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
| | - Hui Mao
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, USA
| | - Shenghong Ju
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
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14
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Fields GB. Mechanisms of Action of Novel Drugs Targeting Angiogenesis-Promoting Matrix Metalloproteinases. Front Immunol 2019; 10:1278. [PMID: 31214203 PMCID: PMC6558196 DOI: 10.3389/fimmu.2019.01278] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 05/20/2019] [Indexed: 12/16/2022] Open
Abstract
Angiogenesis is facilitated by the proteolytic activities of members of the matrix metalloproteinase (MMP) family. More specifically, MMP-9 and MT1-MMP directly regulate angiogenesis, while several studies indicate a role for MMP-2 as well. The correlation of MMP activity to tumor angiogenesis has instigated numerous drug development programs. However, broad-based and Zn2+-chelating MMP inhibitors have fared poorly in the clinic. Selective MMP inhibition by antibodies, biologicals, and small molecules has utilized unique modes of action, such as (a) binding to protease secondary binding sites (exosites), (b) allosterically blocking the protease active site, or (c) preventing proMMP activation. Clinical trials have been undertaken with several of these inhibitors, while others are in advanced pre-clinical stages. The mechanistically non-traditional MMP inhibitors offer treatment strategies for tumor angiogenesis that avoid the off-target toxicities and lack of specificity that plagued Zn2+-chelating inhibitors.
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Affiliation(s)
- Gregg B Fields
- Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, FL, United States.,Department of Chemistry, The Scripps Research Institute/Scripps Florida, Jupiter, FL, United States
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15
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Fischer T, Senn N, Riedl R. Design and Structural Evolution of Matrix Metalloproteinase Inhibitors. Chemistry 2019; 25:7960-7980. [DOI: 10.1002/chem.201805361] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 01/09/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Thomas Fischer
- Center of Organic and Medicinal Chemistry, Institute of Chemistry, and BiotechnologyZurich University of Applied Sciences (ZHAW) Einsiedlerstrasse 31 8820 Wädenswil Switzerland
| | - Nicole Senn
- Center of Organic and Medicinal Chemistry, Institute of Chemistry, and BiotechnologyZurich University of Applied Sciences (ZHAW) Einsiedlerstrasse 31 8820 Wädenswil Switzerland
| | - Rainer Riedl
- Center of Organic and Medicinal Chemistry, Institute of Chemistry, and BiotechnologyZurich University of Applied Sciences (ZHAW) Einsiedlerstrasse 31 8820 Wädenswil Switzerland
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16
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Stansborough RL, Bateman EH, Al-Dasooqi N, Bowen JM, Wignall A, Keefe DM, Yeoh AS, Logan RM, Yeoh EEK, Stringer AM, Gibson RJ. Vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFβ), angiostatin, and endostatin are increased in radiotherapy-induced gastrointestinal toxicity. Int J Radiat Biol 2019; 94:645-655. [PMID: 29855218 DOI: 10.1080/09553002.2018.1483588] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE Radiotherapy-induced gut toxicity (RIGT) is a debilitating effect of radiotherapy for cancer, often resulting in significant diarrhea and pain. Previous studies have highlighted roles of the intestinal microvasculature and matrix metalloproteinases (MMPs) in the development of RIGT. We hypothesized vascular mediators would be significantly altered in a dark agouti (DA) rat model of RIGT. Additionally, we aimed to assess the effect of MMP-2 and -9 inhibition on the response of tumor-associated microvascular endothelial cells (TAMECs) to radiation. METHODS DA rats were administered 2.5 Gy abdominal irradiation (3 times/week over 6 weeks). Vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFβ), von Willebrand factor (VWF), angiostatin, and endostatin expression was assessed at 3, 6, and 15 weeks. Additionally, DA rat mammary adenocarcinoma tumor-associated microvascular endothelial cells (TAMECs) were used to assess the effects of radiation (12 Gy) and the MMP inhibitor SB-3CT on MMP, VEGF, and TGFβ expression, and cell viability. RESULTS VEGF mRNA expression was significantly increased in the colon at week 15 (p = .0012), and TGFβ mRNA expression was significantly increased in both the jejunum and colon at week 3 (p = .0280 and p = .0310, respectively). Endostatin immunostaining was significantly increased at week 3 (p = .0046), and angiostatin at 3 and 6 weeks (p = .0022 and p = .0135, respectively). MMP-2 and -9 mRNA and total protein levels were significantly increased following irradiation of TAMECs. Although this increase was significantly attenuated by SB-3CT, it did not significantly alter endothelial cell viability or VEGF and TGFβ mRNA expression. CONCLUSIONS Findings of this study support the involvement of VEGF, TGFβ, angiostatin, endostatin, and MMP-2 in the pathobiology of RIGT. However, the relationship between these mediators is complex and needs further investigation to improve understanding of their therapeutic potential in RIGT.
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Affiliation(s)
| | - Emma H Bateman
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia
| | - Noor Al-Dasooqi
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia
| | - Joanne M Bowen
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia
| | - Anthony Wignall
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia
| | - Dorothy M Keefe
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia
| | - Ann S Yeoh
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia
| | - Richard M Logan
- b Adelaide Dental School , University of Adelaide , Adelaide , Australia
| | - Eric E K Yeoh
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia
| | - Andrea M Stringer
- c Division of Health Sciences , University of South Australia , Adelaide , Australia
| | - Rachel J Gibson
- a Adelaide Medical School , University of Adelaide , Adelaide , Australia.,c Division of Health Sciences , University of South Australia , Adelaide , Australia
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17
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Identification of N-Hydroxycinnamamide analogues and their bio-evaluation against breast cancer cell lines. Biomed Pharmacother 2018; 107:475-483. [PMID: 30107343 DOI: 10.1016/j.biopha.2018.08.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 07/24/2018] [Accepted: 08/06/2018] [Indexed: 11/21/2022] Open
Abstract
The present study demonstrates the identification of N-hydroxycinnamamide derivatives and their anticancer potential against human triple-negative breast cancer cell line MDA-MB‑231, MCF-7 and non-malignant origin cell line, HEK-293 (human embryonic kidney). MTT assay was studied with HEK-293 cell line. Anticancer potential of the N-hydroxycinnamamide derivatives were compared with marked drug Tamoxifen through in vitro study. The compound numbers 3b and 3h exhibit most potent activity against antagonistic breast cancer cells (MDA-MB-231) with IC5013μM and 5μM respectively. Compound 3h promotes DNA fragmentation and induction of apoptosis. Furthermore, loss of mitochondrial membrane potential induced by compound 3h. The major mechanism of compound 3h for anti-breast cancer activity was probably initiation of reactive oxygen species (ROS) in cancer cells thereby persuading apoptotic cell deaths in cancer cells.
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18
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Xin X, Ding Y, Yang Y, Fu X, Zhou J, McKee CM, Muschel RJ, Gale RP, Apperley JF, Xu D. Protease nexin-1 prevents growth of human B cell lymphoma via inhibition of sonic hedgehog signaling. Blood Cancer J 2018; 8:24. [PMID: 29483508 PMCID: PMC5827524 DOI: 10.1038/s41408-018-0063-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 01/07/2018] [Accepted: 01/15/2018] [Indexed: 11/17/2022] Open
Affiliation(s)
- Xiangke Xin
- Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Yunchuan Ding
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Ying Yang
- Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Xing Fu
- Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Jianfeng Zhou
- Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Chad M McKee
- Gray Institute of Radiation Oncology and Biology, Medical Science Division, University of Oxford, Oxford, UK
| | - Ruth J Muschel
- Gray Institute of Radiation Oncology and Biology, Medical Science Division, University of Oxford, Oxford, UK
| | - Robert P Gale
- Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Imperial College London, Du Cane road, London, W12 0HS, UK
| | - Jane F Apperley
- Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Imperial College London, Du Cane road, London, W12 0HS, UK
| | - Danmei Xu
- Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
- Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Imperial College London, Du Cane road, London, W12 0HS, UK.
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19
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Zhang W, Zhou P, Meng A, Zhang R, Zhou Y. Down-regulating Myoferlin inhibits the vasculogenic mimicry of melanoma via decreasing MMP-2 and inducing mesenchymal-to-epithelial transition. J Cell Mol Med 2017; 22:1743-1754. [PMID: 29164766 PMCID: PMC5824422 DOI: 10.1111/jcmm.13455] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 10/14/2017] [Indexed: 12/14/2022] Open
Abstract
Vasculogenic mimicry (VM) constitutes a novel approach for tumour blood supply and contributes to tumour metastasis and poor prognosis in patients with melanoma. Myoferlin (MYOF), a type II membrane protein involved in membrane regeneration and repair, is elevated in several malignant tumours, especially in advanced melanomas. This study aims to investigate the role and mechanism of MYOF in the regulation of VM. VM structures were found in 14 of 52 tested melanoma samples, and high MYOF expression correlated with VM structures. According to Kaplan–Meier survival curves, VM channels and elevated MYOF expression both correlated with poor prognosis in melanoma patients. Down‐regulation of MYOF by siRNA severely impaired the capability of A375 cells to form VM structures in vitro. Further studies demonstrated MYOF knockdown inhibited cell migration and invasion, which is required for VM formation, via decreasing MMP‐2 expression as evidenced by Western blotting, RT‐RCP and ELISA results. SB‐3CT, a specific inhibitor of MMP‐2, showed similar inhibiting effects with siMYOF, further supporting that MYOF down‐regulation inhibits MMP‐2 expression to affect VM formation. Moreover, MYOF knockdown suppress VM formation by A375 cells by inducing mesenchymal‐to‐epithelial transition (MET). After down‐regulating MYOF, focal adhesions were enlarged and A375 cells developed into a clear epithelial morphology. Such cells acquired the expression of E‐cadherin at adherens junctions along with a loss of mesenchymal markers, such as Vimentin and Twist1. In conclusion, MYOF plays an important role in VM and knockdown of MYOF suppresses VM formation via decreasing MMP‐2 and inducing MET in A375 melanoma cells.
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Affiliation(s)
- Wenxue Zhang
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Ping Zhou
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Ai Meng
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Rongxin Zhang
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Yan Zhou
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
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20
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Testero SA, Granados C, Fernández D, Gallego P, Covaleda G, Reverter D, Vendrell J, Avilés FX, Pallarès I, Mobashery S. Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library. ACS Med Chem Lett 2017; 8:1122-1127. [PMID: 29057062 DOI: 10.1021/acsmedchemlett.7b00346] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 09/22/2017] [Indexed: 12/22/2022] Open
Abstract
Metallocarboxypeptidases (MCPs) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site. This binding leads to a chemical reaction that covalently modifies the catalytic Glu270. These results highlight the importance of combined structural, biophysical, and biochemical evaluation of inhibitors in design strategies for the development of spectroscopically nonsilent probes as effective beacons for in vitro, in cellulo, and/or in vivo localization in clinical and industrial applications.
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Affiliation(s)
- Sebastián A. Testero
- Department
of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Carla Granados
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - Daniel Fernández
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - Pablo Gallego
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - Giovanni Covaleda
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - David Reverter
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - Josep Vendrell
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - Francesc X. Avilés
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - Irantzu Pallarès
- Departament
de Bioquímica i Biologia Molecular, Facultat de Biociències,
and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
| | - Shahriar Mobashery
- Department
of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
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21
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Du HT, Du LL, Tang XL, Ge HY, Liu P. Blockade of MMP-2 and MMP-9 inhibits corneal lymphangiogenesis. Graefes Arch Clin Exp Ophthalmol 2017; 255:1573-1579. [PMID: 28669039 DOI: 10.1007/s00417-017-3651-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 02/13/2017] [Accepted: 03/20/2017] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To investigate the roles of a selective MMP-2 and -9 inhibitor (SB-3CT) in corneal inflammatory lymphangiogenesis. METHODS The expression of MMP-2 and -9 in the cornea after suture inplacement, treated with SB-3CT or negative control, was detected by real-time polymerase chain reaction (PCR). Inflammatory corneal neovascularization (NV) was induced by corneal suture placement. Mice were treated with SB-3CT eye drops (twice daily for 1 week, 5 μL per drop; 50, 100, or 200 μM). The outgrowth of blood and lymphatic vessels, and macrophage recruitment were analyzed by immunofluorescence assay. The expressions of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were tested by real-time PCR. RESULTS MMP-2 and -9 expression were suppressed significantly by treatment with SB-3CT. The data demonstrated, for the first time, that SB-3CT strongly reduced corneal lymphangiogenesis and macrophage infiltration during inflammation. Furthermore, expressions of VEGF-C and its receptor VEGFR-3 were significantly inhibited by SB-3CT during corneal lymphangiogenesis. CONCLUSIONS These novel findings indicated that blockade of MMP-2 and -9 could inhibit lymphangiogenesis. Further investigation of this factor may provide novel therapies for transplant rejection and other lymphatic disorders.
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Affiliation(s)
- Hai-Tao Du
- Department of Ophthalmology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, 150001, China
| | - Ling-Ling Du
- Department of Ophthalmology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, 150001, China
| | - Xian-Ling Tang
- Department of Ophthalmology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, 150001, China
| | - Hong-Yan Ge
- Department of Ophthalmology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, 150001, China
| | - Ping Liu
- Department of Ophthalmology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, 150001, China.
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22
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Li W, Qian L, Lin J, Huang G, Hao N, Wei X, Wang W, Liang J. CD44 regulates prostate cancer proliferation, invasion and migration via PDK1 and PFKFB4. Oncotarget 2017; 8:65143-65151. [PMID: 29029419 PMCID: PMC5630319 DOI: 10.18632/oncotarget.17821] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 04/05/2017] [Indexed: 12/12/2022] Open
Abstract
Our recent studies have shown that CD44, a cell-surface protein with functions in many biologic processes, involved in glucose metabolism of prostate cancer cells. However, the molecular mechanisms of the regulation need to be further elucidated. In present study, LNCaP cells infected with lentivirus vector overexpressing CD44. The expression levels of key enzymes in glucose metabolism known as PDK1 and PFKFB4 were determined using QRT-PCR and western blot. PDK1 and PFKFB4 in LNCaP and PC3 cells were knocked down with shRNA respectively, and then cell proliferation, invasion and cell migration assay were performed. We found that overexpression of CD44 increased expression levels of PDK1 and PFKFB4 in LNCaP cells. Silencing of PDK1 and PFKFB4 could decrease cell proliferation, inhibit invasion and migration ability of prostate cancer cells. In addition, CD44 inhibitor could decrease glucose consumption and increase ROS levels of PC-3 cells significantly, as well as sensitize PC-3 cells to docetaxel. Taken together, CD44 could modulate aggressive phenotype of prostate cancer cells, by regulation of the expression of PDK1 and PFKFB4. CD44 may be a novel potential therapeutic target.
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Affiliation(s)
- Wei Li
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
| | - Li Qian
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
| | - Junhao Lin
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
| | - Guihai Huang
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
| | - Nan Hao
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
| | - Xiuwang Wei
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
| | - Wei Wang
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
| | - Jianbo Liang
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, NanNing, China
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23
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Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 148:355-420. [PMID: 28662828 DOI: 10.1016/bs.pmbts.2017.04.003] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes that degrade various proteins in the extracellular matrix (ECM). MMPs may also regulate the activity of membrane receptors and postreceptor signaling mechanisms and thereby affect cell function. The MMP family includes collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs. Inactive proMMPs are cleaved by other MMPs or proteases into active MMPs, which interact with various protein substrates in ECM and cell surface. MMPs regulate important biological processes such as vascular remodeling and angiogenesis and may be involved in the pathogenesis of cardiovascular disorders such as hypertension, atherosclerosis, and aneurysm. The role of MMPs is often assessed by measuring their mRNA expression, protein levels, and proteolytic activity using gel zymography. MMP inhibitors are also used to assess the role of MMPs in different biological processes and pathological conditions. MMP activity is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP balance could determine the net MMP activity, ECM turnover, and tissue remodeling. Also, several synthetic MMP inhibitors have been developed. Synthetic MMP inhibitors include a large number of zinc-binding globulins (ZBGs), in addition to non-ZBGs and mechanism-based inhibitors. MMP inhibitors have been proposed as potential tools in the management of osteoarthritis, cancer, and cardiovascular disorders. However, most MMP inhibitors have broad-spectrum actions on multiple MMPs and could cause undesirable musculoskeletal side effects. Currently, doxycycline is the only MMP inhibitor approved by the Food and Drug Administration. New generation biological and synthetic MMP inhibitors may show greater MMP specificity and fewer side effects and could be useful in targeting specific MMPs, reducing unrestrained tissue remodeling, and the management of MMP-related pathological disorders.
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24
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Meisel JE, Chang M. Selective small-molecule inhibitors as chemical tools to define the roles of matrix metalloproteinases in disease. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:2001-2014. [PMID: 28435009 DOI: 10.1016/j.bbamcr.2017.04.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/15/2017] [Accepted: 04/17/2017] [Indexed: 12/22/2022]
Abstract
The focus of this article is to highlight novel inhibitors and current examples where the use of selective small-molecule inhibitors has been critical in defining the roles of matrix metalloproteinases (MMPs) in disease. Selective small-molecule inhibitors are surgical chemical tools that can inhibit the targeted enzyme; they are the method of choice to ascertain the roles of MMPs and complement studies with knockout animals. This strategy can identify targets for therapeutic development as exemplified by the use of selective small-molecule MMP inhibitors in diabetic wound healing, spinal cord injury, stroke, traumatic brain injury, cancer metastasis, and viral infection. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
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25
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Tan W, Zhu S, Cao J, Zhang L, Li W, Liu K, Zhong J, Shang C, Chen Y. Inhibition of MMP-2 Expression Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinoma by Suppressing the PI3K/AKT/mTOR Pathway. Oncol Res 2017; 25:1543-1553. [PMID: 28276313 PMCID: PMC7841021 DOI: 10.3727/096504017x14886444100783] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Sorafenib has been globally approved as the standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, the response rate of HCC patients to sorafenib is limited because of tumor recurrence and metastasis. Therefore, seeking combined therapeutic strategies with sorafenib is necessary to improve the antitumor efficiency. Here we demonstrated that expression of MMP-2 is positively correlated with the migration ability of HCC cells. Cells with a higher MMP-2 expression (SK-HEP-1 cells) were less sensitive to sorafenib than those with lower MMP-2 expression (HepG2 cells). Cotreatment of cells with SB-3CT and sorafenib more strongly inhibited migration ability than with sorafenib treatment alone in both HCC cells with high and low expression of MMP-2. In vivo cell metastasis experiments confirmed the synergistic effects of sorafenib and SB-3CT in reducing lung metastasis of SK-HEP-1 cells. Mechanistically, we showed that the synergistic antitumor effect may be attributed to inhibition of the PI3K/AKT/mTOR signaling pathway, but not the RAF/MEK/ERK signaling pathway. With these results taken together, the current study demonstrates that inhibiting MMP-2 expression can enhance the antitumor effect of sorafenib in HCC cells with a high MMP-2 expression, which may provide a novel strategy to improve therapeutic efficiency in HCC.
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26
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Grünwald B, Vandooren J, Gerg M, Ahomaa K, Hunger A, Berchtold S, Akbareian S, Schaten S, Knolle P, Edwards DR, Opdenakker G, Krüger A. Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow. Mol Cancer Res 2016; 14:1147-1158. [PMID: 27489361 DOI: 10.1158/1541-7786.mcr-16-0180] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 06/24/2016] [Indexed: 02/06/2023]
Abstract
Matrix metalloproteinase 9 (MMP-9/Gelatinase B) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and plays a central role in tumor cell invasion and metastasis. Here we complemented mechanistic insights in the cancer biology of MMP-9 and investigated the effects of specific long-term loss-of-function, by genetic ablation, of MMP-9 on PDAC initiation and progression in the well-established KPC mouse model of spontaneous PDAC. Tumor growth and progression were analyzed by histopathology and IHC. Invasive growth of PDAC cells was analyzed by both in vitro (proliferation, survival, migration, invasion assays) and in vivo (experimental metastasis assays) methods. Retroviral shRNAi was used to knockdown target genes (MMP-9, IL6R). Gene expression was analyzed by qRT-PCR, immunoblot, ELISA, in situ hybridization, and zymography. PDAC tumors from MMP-9-deficient mice were dramatically larger, more invasive, and contained more stroma. Yet, ablation of MMP-9 in PDAC cells did not directly promote invasive growth. Interestingly, systemic ablation of MMP-9 led to increased IL6 levels resulting from abrogation of MMP-9-dependent SCF signaling in the bone marrow. IL6 levels in MMP-9-/- mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL6 receptor (IL6R). Interference with IL6R blocked the increased invasion and metastasis of PDAC cells in MMP-9-deficient hosts. In conclusion, ablation of systemic MMP-9 initiated fatal communication between maintenance of physiological functions of MMP-9 in the bone marrow and invasive growth of PDAC via the IL6/IL6R/STAT3 axis. IMPLICATIONS Thus, the beneficial effects of host MMP-9 on PDAC are an important caveat for the use of systemic MMP-9 inhibitors in cancer. Mol Cancer Res; 14(11); 1147-58. ©2016 AACR.
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Affiliation(s)
- Barbara Grünwald
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany
| | - Jennifer Vandooren
- KU Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium
| | - Michael Gerg
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany
| | - Kaarin Ahomaa
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany
| | - Annique Hunger
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany
| | - Sonja Berchtold
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany
| | - Sophia Akbareian
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk, United Kingdom
| | - Susanne Schaten
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany
| | - Percy Knolle
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany
| | - Dylan R Edwards
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk, United Kingdom
| | - Ghislain Opdenakker
- KU Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium
| | - Achim Krüger
- Klinikum rechts der Isar der Technischen Universität München, Institut für Molekulare Immunologie und Experimentelle Onkologie, München, Germany.
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27
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Influence of Immune Myeloid Cells on the Extracellular Matrix During Cancer Metastasis. CANCER MICROENVIRONMENT 2016; 9:45-61. [PMID: 26956475 PMCID: PMC4842183 DOI: 10.1007/s12307-016-0181-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 02/12/2016] [Indexed: 01/04/2023]
Abstract
The extracellular matrix (ECM) is one of the most important components within the tumor microenvironment that supports cancer development and metastasis. Under normal physiological conditions, the ECM is a tightly regulated network providing structural and biochemical support. However, the ECM becomes highly disorganized during neoplastic progression and consequently, stimulates cancer cell transformation, growth and spread. Cancer development and progression is also known to greatly benefit from the support of immune myeloid cells, which have multiple pro-tumorigenic functions including promoting tumor growth, migration and invasion, stimulating angiogenesis and suppressing anti-tumor responses. An increasing number of studies have shown that myeloid cells alter the ECM to support metastatic cancer progression and in turn, the ECM can influence the function of infiltrating myeloid cells. However, the exact nature of this relationship, such as the mechanisms employed and their molecular targets remains unclear. This review discusses evidence for the reciprocal dependence of myeloid cells and the tumor ECM for efficient tumor development and explores potential mechanisms involved in these interactions. A better understanding of this relationship has exciting implications for the development of new therapeutic treatments for metastatic cancer.
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28
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Sztukowska MN, Ojo A, Ahmed S, Carenbauer AL, Wang Q, Shumway B, Jenkinson HF, Wang H, Darling DS, Lamont RJ. Porphyromonas gingivalis initiates a mesenchymal-like transition through ZEB1 in gingival epithelial cells. Cell Microbiol 2016; 18:844-58. [PMID: 26639759 DOI: 10.1111/cmi.12554] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 11/18/2015] [Accepted: 12/01/2015] [Indexed: 12/28/2022]
Abstract
The oral anaerobe Porphyromonas gingivalis is associated with the development of cancers including oral squamous cell carcinoma (OSCC). Here, we show that infection of gingival epithelial cells with P. gingivalis induces expression and nuclear localization of the ZEB1 transcription factor, which controls epithelial-mesenchymal transition. P. gingivalis also caused an increase in ZEB1 expression as a dual species community with Fusobacterium nucleatum or Streptococcus gordonii. Increased ZEB1 expression was associated with elevated ZEB1 promoter activity and did not require suppression of the miR-200 family of microRNAs. P. gingivalis strains lacking the FimA fimbrial protein were attenuated in their ability to induce ZEB1 expression. ZEB1 levels correlated with an increase in expression of mesenchymal markers, including vimentin and MMP-9, and with enhanced migration of epithelial cells into matrigel. Knockdown of ZEB1 with siRNA prevented the P. gingivalis-induced increase in mesenchymal markers and epithelial cell migration. Oral infection of mice by P. gingivalis increased ZEB1 levels in gingival tissues, and intracellular P. gingivalis were detected by antibody staining in biopsy samples from OSCC. These findings indicate that FimA-driven ZEB1 expression could provide a mechanistic basis for a P. gingivalis contribution to OSCC.
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Affiliation(s)
- Maryta N Sztukowska
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Akintunde Ojo
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Saira Ahmed
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Anne L Carenbauer
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Qian Wang
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Brain Shumway
- Department of Surgical and Hospital Dentistry, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | | | - Huizhi Wang
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Douglas S Darling
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Richard J Lamont
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
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29
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Nuti E, Cantelmo AR, Gallo C, Bruno A, Bassani B, Camodeca C, Tuccinardi T, Vera L, Orlandini E, Nencetti S, Stura EA, Martinelli A, Dive V, Albini A, Rossello A. N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity. J Med Chem 2015; 58:7224-40. [DOI: 10.1021/acs.jmedchem.5b00367] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Elisa Nuti
- Dipartimento
di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Anna Rita Cantelmo
- Science
and Technological Park, IRCCS MultiMedica, via Fantoli 16/15, 20138 Milan, Italy
| | - Cristina Gallo
- Laboratory
of Translational Research, IRCCS Arcispedale Santa Maria Nuova, viale
Risorgimento 80, 42121 Reggio Emilia, Italy
| | - Antonino Bruno
- Science
and Technological Park, IRCCS MultiMedica, via Fantoli 16/15, 20138 Milan, Italy
| | - Barbara Bassani
- Science
and Technological Park, IRCCS MultiMedica, via Fantoli 16/15, 20138 Milan, Italy
| | - Caterina Camodeca
- Division
of Immunology, Transplants and Infectious Diseases, IRCCS San Raffaele, via Olgettina 60, 20132 Milano, Italy
| | - Tiziano Tuccinardi
- Dipartimento
di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Laura Vera
- CEA,
iBiTec-S, Service d’Ingenierie Moleculaire des Proteines (SIMOPRO), CE-Saclay 91191 Gif sur Yvette Cedex, France
| | | | - Susanna Nencetti
- Dipartimento
di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Enrico A. Stura
- CEA,
iBiTec-S, Service d’Ingenierie Moleculaire des Proteines (SIMOPRO), CE-Saclay 91191 Gif sur Yvette Cedex, France
| | - Adriano Martinelli
- Dipartimento
di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Vincent Dive
- CEA,
iBiTec-S, Service d’Ingenierie Moleculaire des Proteines (SIMOPRO), CE-Saclay 91191 Gif sur Yvette Cedex, France
| | - Adriana Albini
- Laboratory
of Translational Research, IRCCS Arcispedale Santa Maria Nuova, viale
Risorgimento 80, 42121 Reggio Emilia, Italy
| | - Armando Rossello
- Dipartimento
di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy
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30
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Mehner C, Hockla A, Miller E, Ran S, Radisky DC, Radisky ES. Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget 2015; 5:2736-49. [PMID: 24811362 PMCID: PMC4058041 DOI: 10.18632/oncotarget.1932] [Citation(s) in RCA: 263] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options.
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31
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Primitive macrophages control HSPC mobilization and definitive haematopoiesis. Nat Commun 2015; 6:6227. [DOI: 10.1038/ncomms7227] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 01/07/2015] [Indexed: 12/28/2022] Open
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32
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Lee M, Hesek D, Noll BC, Oliver AG, Mobashery S. Enantiomers of a selective gelatinase inhibitor: (R)- and (S)-2-[(4-phenoxyphenyl)sulfonylmethyl]thiirane. ACTA CRYSTALLOGRAPHICA SECTION C-STRUCTURAL CHEMISTRY 2014; 70:1003-6. [PMID: 25370094 DOI: 10.1107/s2053229614021214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 09/23/2014] [Indexed: 11/10/2022]
Abstract
The compound 2-[(4-phenoxyphenyl)sulfonylmethyl]thiirane, C15H14O3S2, a selective gelatinase inhibitor, was synthesized and structurally characterized. Two crystals were analyzed, one each for the R and S enantiomers, and the results were compared with the previously reported structure of the racemate. The enantiomerically pure compounds both crystallize with Z' = 2 in the space group P2₁, while the racemic mixture crystallizes with Z' = 1 in the space group P2₁/c, with disorder in the position of the thiirane group. This disorder accommodates both molecules for each of the enantiomerically pure crystals, showing good overlap of the molecules of the pure enantiomorphs with the components of the centrosymmetric structure.
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Affiliation(s)
- Mijoon Lee
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA
| | - Dusan Hesek
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA
| | - Bruce C Noll
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA
| | - Allen G Oliver
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA
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Abstract
Targeting prostate cancer metastasis has very high therapeutic potential. Prostate cancer is the second most common cause of cancer death among men in the USA, and death results from the development of metastatic disease. In order to metastasize, cancer cells must complete a series of steps that together constitute the metastatic cascade. Each step therefore offers the opportunity for therapeutic targeting. However, practical limitations have served as limiting roadblocks to successfully targeting the metastatic cascade. They include our still-emerging understanding of the underlying biology, as well as the fact that many of the dysregulated processes have critical functionality in otherwise normal cells. We provide a discussion of the underlying biology, as it relates to therapeutic targeting. Therapeutic inroads are rapidly being made, and we present a series of case studies to highlight key points. Finally, future perspectives related to drug discovery for antimetastatic agents are discussed.
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Tang SC, Chen YC. Novel therapeutic targets for pancreatic cancer. World J Gastroenterol 2014; 20:10825-10844. [PMID: 25152585 PMCID: PMC4138462 DOI: 10.3748/wjg.v20.i31.10825] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/13/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.
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Alizadeh AM, Shiri S, Farsinejad S. Metastasis review: from bench to bedside. Tumour Biol 2014; 35:8483-523. [PMID: 25104089 DOI: 10.1007/s13277-014-2421-z] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 07/29/2014] [Indexed: 12/19/2022] Open
Abstract
Cancer is the final result of uninhibited cell growth that involves an enormous group of associated diseases. One major aspect of cancer is when cells attack adjacent components of the body and spread to other organs, named metastasis, which is the major cause of cancer-related mortality. In developing this process, metastatic cells must successfully negotiate a series of complex steps, including dissociation, invasion, intravasation, extravasation, and dormancy regulated by various signaling pathways. In this review, we will focus on the recent studies and collect a comprehensive encyclopedia in molecular basis of metastasis, and then we will discuss some new potential therapeutics which target the metastasis pathways. Understanding the new aspects on molecular mechanisms and signaling pathways controlling tumor cell metastasis is critical for the development of therapeutic strategies for cancer patients that would be valuable for researchers in both fields of molecular and clinical oncology.
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Affiliation(s)
- Ali Mohammad Alizadeh
- Cancer Research Center, Tehran University of Medical Sciences, Tehran, 1419733141, Iran,
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36
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O'Sullivan S, Medina C, Ledwidge M, Radomski MW, Gilmer JF. Nitric oxide-matrix metaloproteinase-9 interactions: biological and pharmacological significance--NO and MMP-9 interactions. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:603-17. [PMID: 24333402 DOI: 10.1016/j.bbamcr.2013.12.006] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 12/02/2013] [Accepted: 12/05/2013] [Indexed: 12/24/2022]
Abstract
Nitric oxide (NO) and matrix metalloproteinase 9 (MMP-9) levels are found to increase in inflammation states and in cancer, and their levels may be reciprocally modulated. Understanding interactions between NO and MMP-9 is of biological and pharmacological relevance and may prove crucial in designing new therapeutics. The reciprocal interaction between NO and MMP-9 have been studied for nearly twenty years but to our knowledge, are yet to be the subject of a review. This review provides a summary of published data regarding the complex and sometimes contradictory effects of NO on MMP-9. We also analyse molecular mechanisms modulating and mediating NO-MMP-9 interactions. Finally, a potential therapeutic relevance of these interactions is presented.
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Fabre B, Filipiak K, Coderch C, Zapico JM, Carbajo RJ, Schott AK, Pineda-Lucena A, de Pascual-Teresa B, Ramos A. New clicked thiirane derivatives as gelatinase inhibitors: the relevance of the P1′ segment. RSC Adv 2014. [DOI: 10.1039/c3ra46402d] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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38
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Ding D, Lichtenwalter K, Pi H, Mobashery S, Chang M. Characterization of a selective inhibitor for matrix metalloproteinase-8 (MMP-8). MEDCHEMCOMM 2014. [DOI: 10.1039/c4md00172a] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
MMP-8 has been implicated in various diseases using a reported selective MMP-8 inhibitor that is actually a broad-spectrum MMP inhibitor.
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Affiliation(s)
- Derong Ding
- Department of Chemistry and Biochemistry
- University of Notre Dame
- Notre Dame, USA
| | | | - Hualiang Pi
- Department of Chemistry and Biochemistry
- University of Notre Dame
- Notre Dame, USA
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry
- University of Notre Dame
- Notre Dame, USA
| | - Mayland Chang
- Department of Chemistry and Biochemistry
- University of Notre Dame
- Notre Dame, USA
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Inaba H, Sugita H, Kuboniwa M, Iwai S, Hamada M, Noda T, Morisaki I, Lamont RJ, Amano A. Porphyromonas gingivalis promotes invasion of oral squamous cell carcinoma through induction of proMMP9 and its activation. Cell Microbiol 2013; 16:131-45. [PMID: 23991831 DOI: 10.1111/cmi.12211] [Citation(s) in RCA: 154] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 08/02/2013] [Accepted: 08/15/2013] [Indexed: 02/06/2023]
Abstract
Recent epidemiological studies have revealed a significant association between periodontitis and oral squamous cell carcinoma (OSCC). Furthermore, matrix metalloproteinase 9 (MMP9) is implicated in the invasion and metastasis of tumour cells. We examined the involvement of Porphyromonas gingivalis, a periodontal pathogen, in OSCC invasion through induced expression of proMMP and its activation. proMMP9 was continuously secreted from carcinoma SAS cells, while P. gingivalis infection increased proenzyme expression and subsequently processed it to active MMP9 in culture supernatant, which enhanced cellular invasion. In contrast, Fusobacterium nucleatum, another periodontal organism, failed to demonstrate such activities. The effects of P. gingivalis were observed with highly invasive cells, but not with the low invasivetype. P. gingivalis also stimulated proteinase-activated receptor 2 (PAR2) and enhanced proMMP9 expression, which promoted cellular invasion. P. gingivalis mutants deficient in gingipain proteases failed to activate MMP9. Infected SAS cells exhibited activation of ERK1/2, p38, and NF-kB, and their inhibitors diminished both proMMP9-overexpression and cellular invasion. Together, our results show that P. gingivalis activates the ERK1/2-Ets1, p38/HSP27, and PAR2/NF-kB pathways to induce proMMP9 expression, after which the proenzyme is activated by gingipains to promote cellular invasion of OSCC cell lines. These findings suggest a novel mechanism of progression and metastasis of OSCC associated with periodontitis.
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Affiliation(s)
- Hiroaki Inaba
- Department of Oral Frontier Biology, Center for Frontier Oral Science, Osaka University Graduate School of Dentistry, Suita, Osaka, 565-0871, Japan
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40
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Suppression of plasminogen activators and the MMP-2/-9 pathway by a Zanthoxylum avicennae extract to inhibit the HA22T human hepatocellular carcinoma cell migration and invasion effects in vitro and in vivo via phosphatase 2A activation. Biosci Biotechnol Biochem 2013; 77:1814-21. [PMID: 24018669 DOI: 10.1271/bbb.130060] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
This study shows that the ECM degradation-associated pathway, including uPA and tPA and the downstream MMP-2/-9 protein, was significantly suppressed in HA22T cells treated with a Zanthoxylum avicennae extract (YBBE). The endogenous inhibitors, including TIMP-1/-2 and PAI-1, were enhanced in HA22T cells by the YBBE treatment. The expression of MMP-2/-9 and TIMP-1/-2 was respectively assessed by using RT-PCR and a zymography assay. The mRNA levels and enzymatic activity of MMP-2/-9 were down-regulated by the YBBE treatment in a dose-dependent manner, while the TIMP-1/-2 levels were conversely markedly increased. The PP2A siRNA or PP2A inhibitor totally reversed the YBBE effects, confirming the essential role of PP2A in YBBE inhibiting the HA22T cell migration and invasion effects. Xenografted animal experiments on nude mice demonstrated similiar results to the in vitro system. Both the in vitro and in vivo models clearly demonstrate that YBBE inhibited the highly metastatic HA22T liver cancer cell migration and invasion effects through PP2A activation.
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41
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Weinspach D, Seubert B, Schaten S, Honert K, Sebens S, Altevogt P, Krüger A. Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization, and metastatic growth. Clin Exp Metastasis 2013; 31:87-100. [PMID: 24002299 DOI: 10.1007/s10585-013-9613-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 08/15/2013] [Indexed: 01/03/2023]
Abstract
Expression of the L1 cell adhesion molecule (L1CAM) is frequently increased in cancer patients compared to healthy individuals and also linked with bad prognosis of solid tumours. Previously, we could show that full-length L1CAM promotes metastasis formation via up-regulation of gelatinolytic activity in fibrosarcoma. In this study, we aimed to extend this finding to haematogenous malignancies and carcinomas, and to specifically elucidate the impact of L1CAM on major steps of the metastatic cascade. In a well-established T-cell lymphoma spontaneous metastasis model, silencing of L1CAM significantly improved survival of the mice, while intradermal tumour growth remained unaltered. This correlated with significantly decreased spontaneous metastasis formation. L1CAM suppression abrogated the metastatic potential of T-cell lymphoma as well as carcinoma cells as demonstrated by reduced migration and invasion in vitro and reduced formation of experimental metastasis in vivo. At the molecular level, silencing of L1CAM led to reduced expression of gelatinases MMP-2 and -9 in vitro and decreased gelatinolytic activity in primary tumours and metastases in vivo. In accordance, knock down of L1CAM had similar suppressive effects on migration, invasion and in vivo-gelatinolytic activity as treatment with the specific gelatinase inhibitor SB-3CT. This newly discovered impact of L1CAM on distinct steps of the metastatic cascade and MMP activity highlights the potential of possible L1CAM-directed therapies to inhibit metastatic spread.
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Affiliation(s)
- Dirk Weinspach
- Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar, Technische Universität München, 81675, Munich, Germany
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42
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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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43
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Rodriguez Faba O, Palou-Redorta J, Fernández-Gómez JM, Algaba F, Eiró N, Villavicencio H, Vizoso FJ. Matrix Metalloproteinases and Bladder Cancer: What is New? ISRN UROLOGY 2012; 2012:581539. [PMID: 22852097 PMCID: PMC3407627 DOI: 10.5402/2012/581539] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 06/03/2012] [Indexed: 11/23/2022]
Abstract
Urothelial bladder cancer represents a heterogeneous disease with divergent pathways of tumorigenesis. Tumor invasion and progression are a multifactorial process promoted by microenvironmental changes that include overexpression of matrix metalloproteinases (MMPs). Recent data clearly challenge the classic dogma that MMPs promote metastasis only by modulating the remodeling of extracellular matrix. Indeed, MMPs have also been attributed as an impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines. Levels of the different MMPs can be measured in several sample types, including tissue, blood (serum and plasma), and urine, and using different methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay, and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with cytology. Although MMP inhibitors have shown limited efficacy, advances in the understanding of the complex physiologic and pathologic roles of MMPs might permit the development of new MMP-specific and tumor-specific therapies. In this paper we update the understanding of MMPs based on a systematic PubMed search encompassing papers published up to December 2011.
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Affiliation(s)
- O Rodriguez Faba
- Department of Urology, Universitat Autonòma de Barcelona, Barcelona, 08025 Fundació Puigvert, Spain
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44
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Lee M, Ikejiri M, Klimpel D, Toth M, Espahbodi M, Hesek D, Forbes C, Kumarasiri M, Noll BC, Chang M, Mobashery S. Structure-Activity Relationship for Thiirane-Based Gelatinase Inhibitors. ACS Med Chem Lett 2012; 3:490-495. [PMID: 22737278 DOI: 10.1021/ml300050b] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
An extensive structure-activity relationship study with the template of 2-(4-phenoxyphenylsulfonylmethyl)thiirane (1), a potent and highly selective inhibitor for human gelatinases, is reported herein. Syntheses of 65 new analogs, each in multistep processes, allowed for exploration of key structural components of the molecular template. This study reveals that the presence of the sulfonylmethylthiirane and the phenoxyphenyl group were important for gelatinase inhibition. However, para- and some meta-substitutions of the terminal phenyl ring enhanced inhibitory activity, and led to improve metabolic stability. This agrees with the result from metabolism studies with compound 1 that the primary route of biotransformation is oxidation, mainly at the para position of the phenyl ring and alpha position of the sulfonyl group in the aliphatic side chain.
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Affiliation(s)
- Mijoon Lee
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Masahiro Ikejiri
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Dennis Klimpel
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Marta Toth
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Mana Espahbodi
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Dusan Hesek
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Christopher Forbes
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Malika Kumarasiri
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Bruce C. Noll
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Mayland Chang
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556,
United States
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45
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Mauro A, Lipari L, Tortorici S, Leone A, Gerbino A, Buscemi M. Expression of MMP-2 and MMP-9 in odontogenic myxoma in a child: report of a clinical case. Odontology 2012; 101:233-8. [PMID: 22349931 DOI: 10.1007/s10266-011-0056-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 12/06/2011] [Indexed: 10/28/2022]
Abstract
BACKGROUND Odontogenic myxoma (OM) is a benign, locally invasive, non-metastasizing neoplasm of the jaw bones. Despite the benign nature of these lesions, there is a high rate of recurrence and the current recommended therapy, depending on the size and behaviour of the lesion, can vary from curettage with peripheral ostectomy, segmental resection up to radical resections for more aggressive lesions. OM is a rare tumour which occurs predominantly in the third decade of life and it is rare in children. Matrix metalloproteinases (MMPs) are a family of extracellular endopeptidases responsible for the degradation and remodelling of extracellular matrix, they are known to be involved in the progression and invasiveness of many types of tumour. MMPs have been studied in OM because of their well-known role in extracellular matrix degradation, tumour invasion and recurrence. CLINICAL CASE REPORT We report a case of OM in a 6-year-old boy. A conservative excision was accomplished. The mass was excised without affecting the mandibular bone and the inferior alveolar nerve. Curettage and removal of the first right inferior molar were performed. After 6-month follow-up, no evidence of recurrence was found. EXPERIMENTAL DATA We investigated the expression of MMP-2 and MMP-9 in this case of OM in a child. RT-PCR showed the expression of both MMP-2 and MMP-9 mRNAs. Immunohistochemistry showed a weak MMP-2 protein expression while MMP-9 protein was not detected. CONCLUSION In this case of OM in a child, we report lack of recurrence after excision associated with low MMP-2 protein expression and absence of MMP-9. We believe it is worthy to deeply investigate the relationship between MMPs expression and OM behaviour with the aim to use MMPs as prognostic and/or therapeutic markers in OM.
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Affiliation(s)
- Annamaria Mauro
- BioNeC, Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Sezione di Istologia ed Embriologia "Arcangelo Pasqualino di Marineo", Facoltà di Medicina e Chirurgia, Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy,
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46
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Ranasinghe HS, Scheepens A, Sirimanne E, Mitchell MD, Williams CE, Fraser M. Inhibition of MMP-9 Activity following Hypoxic Ischemia in the Developing Brain Using a Highly Specific Inhibitor. Dev Neurosci 2012; 34:417-27. [DOI: 10.1159/000343257] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Accepted: 09/05/2012] [Indexed: 12/28/2022] Open
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47
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Matrix metalloproteinase inhibitors as investigative tools in the pathogenesis and management of vascular disease. EXPERIENTIA SUPPLEMENTUM (2012) 2012; 103:209-79. [PMID: 22642194 DOI: 10.1007/978-3-0348-0364-9_7] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade various components of the extracellular matrix (ECM). MMPs could also regulate the activity of several non-ECM bioactive substrates and consequently affect different cellular functions. Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. Pro-MMPs are cleaved into active MMPs, which in turn act on various substrates in the ECM and on the cell surface. MMPs play an important role in the regulation of numerous physiological processes including vascular remodeling and angiogenesis. MMPs may also be involved in vascular diseases such as hypertension, atherosclerosis, aortic aneurysm, and varicose veins. MMPs also play a role in the hemodynamic and vascular changes associated with pregnancy and preeclampsia. The role of MMPs is commonly assessed by measuring their gene expression, protein amount, and proteolytic activity using gel zymography. Because there are no specific activators of MMPs, MMP inhibitors are often used to investigate the role of MMPs in different physiologic processes and in the pathogenesis of specific diseases. MMP inhibitors include endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, and marimastat. MMP inhibitors have been evaluated as diagnostic and therapeutic tools in cancer, autoimmune disease, and cardiovascular disease. Although several MMP inhibitors have been synthesized and tested both experimentally and clinically, only one MMP inhibitor, i.e., doxycycline, is currently approved by the Food and Drug Administration. This is mainly due to the undesirable side effects of MMP inhibitors especially on the musculoskeletal system. While most experimental and clinical trials of MMP inhibitors have not demonstrated significant benefits, some trials still showed promising results. With the advent of new genetic and pharmacological tools, disease-specific MMP inhibitors with fewer undesirable effects are being developed and could be useful in the management of vascular disease.
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48
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Hua H, Li M, Luo T, Yin Y, Jiang Y. Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci 2011; 68:3853-68. [PMID: 21744247 PMCID: PMC11114831 DOI: 10.1007/s00018-011-0763-x] [Citation(s) in RCA: 195] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Revised: 05/31/2011] [Accepted: 06/21/2011] [Indexed: 02/05/2023]
Abstract
Proteases are crucial for development, tissue remodeling, and tumorigenesis. Matrix metalloproteinases (MMPs) family, in particular, consists of more than 20 members with unique substrates and diverse function. The expression and activity of MMPs in a variety of human cancers have been intensively studied. MMPs have well-recognized roles in the late stage of tumor progression, invasion, and metastasis. However, increasing evidence demonstrates that MMPs are involved earlier in tumorigenesis, e.g., in malignant transformation, angiogenesis, and tumor growth both at the primary and metastatic sites. Recent studies also suggest that MMPs play complex roles in tumor progression. While most MMPs promote tumor progression, some of them may protect the host against tumorigenesis in a context-dependent manner. MMPs have been chosen as promising targets for cancer therapy on the basis of their aberrant up-regulation in malignant tumors and their ability to promote cancer metastasis. Although preclinical studies testing the efficacy of MMP suppression in tumor models were so encouraging, the results of clinical trials in cancer patients have been rather disappointing. Here, we review the complex roles of MMPs and their endogenous inhibitors such as tissue inhibitors of metalloproteinase in tumorigenesis and strategies in suppressing MMPs.
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Affiliation(s)
- Hui Hua
- State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, China
| | - Minjing Li
- State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Luo
- Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yancun Yin
- State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yangfu Jiang
- State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, China
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Gooyit M, Lee M, Schroeder VA, Ikejiri M, Suckow MA, Mobashery S, Chang M. Selective water-soluble gelatinase inhibitor prodrugs. J Med Chem 2011; 54:6676-90. [PMID: 21866961 DOI: 10.1021/jm200566e] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
SB-3CT (1), a selective and potent thiirane-based gelatinase inhibitor, is effective in animal models of cancer metastasis and stroke; however, it is limited by poor aqueous solubility and extensive metabolism. We addressed these issues by blocking the primary site of metabolism and capitalizing on a prodrug strategy to achieve >5000-fold increased solubility. The amide prodrugs were quantitatively hydrolyzed in human blood to a potent gelatinase inhibitor, ND-322 (3). The arginyl amide prodrug (ND-478, 5d) was metabolically stable in mouse, rat, and human liver microsomes. Both 5d and 3 were nonmutagenic in the Ames II mutagenicity assay. The prodrug 5d showed moderate clearance of 0.0582 L/min/kg, remained mostly in the extracellular fluid compartment (Vd = 0.0978 L/kg), and had a terminal half-life of >4 h. The prodrug 5d had superior pharmacokinetic properties than those of 3, making the thiirane class of selective gelatinase inhibitors suitable for intravenous administration in the treatment of acute gelatinase-dependent diseases.
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Affiliation(s)
- Major Gooyit
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
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50
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Qiu LB, Zhou Y, Wang Q, Yang LL, Liu HQ, Xu SL, Qi YH, Ding GR, Guo GZ. Synthetic gelatinases inhibitor attenuates electromagnetic pulse-induced blood–brain barrier disruption by inhibiting gelatinases-mediated ZO-1 degradation in rats. Toxicology 2011; 285:31-8. [DOI: 10.1016/j.tox.2011.03.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Revised: 03/28/2011] [Accepted: 03/31/2011] [Indexed: 10/18/2022]
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