Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023) (original) (raw)
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Structure and Future Prospective of Matrix Metalloproteinases
Experimental Biology, 2021
Matrix metalloproteinases (MMPs) are group of enzymes responsible for the collagen, and protein degradation in extracellular matrix (ECM). Collagen is the main structural component of connective tissue, and its degradation is an important process in the tissue development, remodeling, and repair. MMP family is divided into 6 groups: collagenases, gelatinases, stromelysins, matrilysins, membranetype MMPs, and non-classified MMPs. The MMPs, and MMP inhibitors (MMPI) have multiple biological functions in stages of cancer development. MMPs, and MMPI are extensively examined as potential anticancer medications. The need for selective and metabolically stable MMPs and MMP inhibitors determined the effect of their activity on biological systems. In particular, the relationship of MMPs with the immune system has revealed the potential for the use of MMP inhibitors in therapy. As is known, the degree of invasive growth and metastasis of tumor cells are determined by their ability to cleave all ECM structures of the extracellular matrix-only MMPs can do this. It is important to note that ECM affects the behavior of both cancer cells and stromal, endothelial and immune cells in the environment. The fundamentally important role of ECM is dynamism during tissue homeostasis and the ability to regulate the activation of immune cells.
Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies
International Journal of Developmental Biology, 2004
Over the last years, the relevance of the matrix metalloproteinase (MMP) family in cancer research has grown considerably. These enzymes were initially associated with the invasive properties of tumour cells, owing to their ability to degrade all major protein components of the extracellular matrix (ECM) and basement membranes. However, further studies have demonstrated the implication of MMPs in early steps of tumour evolution, including stimulation of cell proliferation and modulation of angiogenesis. The establishment of causal relationships between MMP overproduction in tumour or stromal cells and cancer progression has prompted the development of clinical trials with a series of inhibitors designed to block the proteolytic activity of these enzymes. Unfortunately, the results derived from using broad-spectrum MMP inhibitors (MMPIs) for treating patients with advanced cancer have been disappointing in most cases. There are several putative explanations for the lack of success of these MMPIs including the recent finding that some MMPs may play a paradoxical protective role in tumour progression. These observations together with the identification of novel functions for MMPs in early stages of cancer have made necessary a reformulation of MMP inhibition strategies. A better understanding of the functional complexity of this proteolytic system and global approaches to identify the relevant MMPs which must be targeted in each individual cancer patient, will be necessary to clarify whether MMP inhibition may be part of future therapies against cancer.
Matrix Metalloproteinase Inhibitors as Anticancer Therapeutics
Current Cancer Drug Targets, 2005
Matrix metalloproteinases (MMPs), also designated as matrixins, play a central role in many biological processes and are involved both in physiologic cellular processes and in pathologic situations such as tumor growth, invasion and metastasis. For more than 30 years MMPs have been considered as promising targets for cancer therapy and a number of different synthetic and natural MMP inhibitors have been identified as cytostatic and anti-angiogenic agents and have begun clinical testing in view of their specific implication in malignant tissues. Although preclinical studies were so compelling to encourage several clinical trials, the past years have seen a consistent number of disappointments and limited success. The critical examination of previous studies shed light on new information about the cellular source, substrates and mode of action of MMPs, focusing the attention of future research on the identification of specific MMP targets in tumors at different stage of tumor progression, both in order to improve efficacy and to reduce the side effect profile. In this review we discuss the current view on the feasibility of MMPs as target for therapeutic intervention in cancer, taking into account that the perspective may be of great value for molecular medicine for the twenty-first century, providing intriguing information about the MMPs as mediators in biology and pathology, and as targets for disease therapies.
Matrix Metalloproteinases and Cancer - Roles in Threat and Therapy
Asian Pacific Journal of Cancer Prevention, 2014
Matrix metalloproteinases (MMPs) are a family of zinc dependent extracellular matrix (ECM) remodelling endopeptidases having the ability to degrade almost all components of extracellular matrix and implicated in various physiological as well as pathological processes. Carcinogenesis is a multistage process in which alteration of the microenvironment is required for conversion of normal tissue to a tumour. Extracellular matrix remodelling proteinases such as MMPs are principal mediators of alterations observed in the microenvironment during carcinogenesis and according to recent concepts not only have roles in invasion or late stages of cancer but also in regulating initial steps of carcinogenesis in a favourable or unfavourable manner. Establishment of relationships between MMP overproduction and cancer progression has stimulated the development of inhibitors that block proteolytic activity of these enzymes. In this review we discuss the MMP general structure, classification, regulation roles in relation to hallmarks of cancer and as targets for therapeutic intervention.
Matrix metalloproteinases: protective roles in cancer
Journal of cellular and molecular medicine, 2011
• Introduction• MMP-3• MMP-8• MMP-9• MMP-12• MMP-19• MMP-26• ConclusionsIntroductionMMP-3MMP-8MMP-9MMP-12MMP-19MMP-26ConclusionsThe original notion that matrix metalloproteinases (MMPs) act as tumour and metastasis-promoting enzymes by clearing a path for tumour cells to invade and metastasize has been challenged in the last decade. It has become clear that MMPs are involved in numerous steps of tumour progression and metastasis, and hence are now considered to be multifaceted proteases. Moreover, more recent experimental evidence indicates that some members of the MMP family behave as tumour-suppressor enzymes and should therefore be regarded as anti-targets in cancer therapy. The complexity of the pro- and anti-tumorigenic and -metastatic functions might partly explain why broad-spectrum MMP inhibitors failed in phase III clinical trials. This review will provide a focussed overview of the published data on the tumour-suppressive behaviour of MMPs.
New approaches to selectively target cancer-associated matrix metalloproteinase activity
Cancer and Metastasis Reviews, 2014
Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.
Biochimica et biophysica acta, 2010
The biological roles of the matrix metalloproteinases (MMPs) have been traditionally associated with the degradation and turnover of most of the components of the extracellular matrix (ECM). This functional misconception has been used for years to explain the involvement of the MMP family in developmental processes, cell homeostasis and disease, and led to clinical trials of MMP inhibitors for the treatment of cancer that failed to meet their endpoints and cast a shadow on MMPs as druggable targets. Accumulated evidence from a great variety of post-trial MMP degradomics studies, ranging from transgenic models to recent state-of-the-art proteomics screens, is changing the dogma about MMP functions. MMPs regulate cell behavior through finely tuned and tightly controlled proteolytic processing of a large variety of signaling molecules that can also have beneficial effects in disease resolution. Moreover, net proteolytic activity relies upon direct interactions between the different pro...
Frontiers in Molecular Biosciences
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate the turnover of extracellular matrix (ECM) components. Gross and La Piere discovered MMPs in 1962 during an experiment on tissue samples from a tadpole’s tail. Several subtypes of MMPs have been identified, depending on their substrate specificity and localization. MMPs are involved as essential molecules in multiple and diverse physiological processes, such as reproduction, embryonic development, bone remodeling, tissue repair, and regulation of inflammatory processes. Its activity is controlled at various levels such as at transcription level, pro-peptide activation level and by the activity of a family of tissue inhibitors of metalloproteinase, endogenous inhibitors of MMPs. Cancer metastasis, which is the spread of a tumor to a distant site, is a complex process that is responsible for the majority of cancer-related death It is considered to be an indicator of cancer metastasis. During metastasis, t...
Metalloproteinases In Medicine, 2016
The development of therapeutic matrix metalloproteinase (MMP) inhibitors has evolved from broad-spectrum peptidomimetic inhibitors with deleterious side effects, to highly selective agents. These range from small molecules to antibodies, antisense inhibitors, and engineered N-terminal tissue inhibitors of metalloproteinase domain. The advances in inhibitor design along with promising new global molecular insights into MMP structures, the protease web, and the role of extracellular matrix in diseases have contributed toward a renewed interest in using MMPs as valid drug targets. This review aims to address the advances and challenges concerning the design, development, and current status of anti-MMP agents in this new era of post-broad-spectrum MMP inhibitors. Highly selective inhibitors of MMPs promise to usher in an era of specific targeting of diseased tissue proteolysis networks, with markedly reduced negative repercussions, and to uncover the molecular and mechanistic roles of MMP isoforms in cancer, inflammation, and infection.