Matrix metalloproteinase inhibitors
Matrix metalloproteinase inhibitors (MMP inhibitors) are therapeutic agents designed to suppress the activity of matrix metalloproteinases (MMPs), enzymes that play a crucial role in the breakdown of the extracellular matrix. This enzymatic activity is often exploited by cancer cells to facilitate tumor invasion and metastasis. MMP inhibitors have been explored in clinical trials for various cancers, including pancreatic, colon, and lung cancers, but their efficacy has often been limited due to a lack of selectivity for specific MMPs. Challenges arise since MMPs are also involved in normal physiological processes, such as wound healing and angiogenesis, necessitating a careful balance in treatment approaches.
Despite the disappointing results of broad-spectrum MMP inhibitors, research continues into developing more selective inhibitors that target specific MMPs like MMP-3, MMP-10, and MMP-9, which are associated with cancer progression and metastasis. Some of the most promising MMP inhibitors can be administered orally, allowing for easier and prolonged treatment. Side effects reported by patients taking these inhibitors include abdominal pain, fever, elevated liver enzymes, and skin reactions. The ongoing research aims not only to improve the effectiveness of these inhibitors but also to minimize adverse effects, ultimately enhancing the prospects for cancer treatment.
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Matrix metalloproteinase inhibitors
DEFINITION: Matrix metalloproteinase (MMP) inhibitors suppress the enzymatic activity of extracellular matrix metalloproteinases (MMPs) secreted by cancer cells.
Cancers treated: Molecular matrix metalloproteinase inhibitors have been in clinical trials for decades. The efficacies of small molecule inhibitors in treating cancers have failed, partly because of a lack of selectivity. Research into alternative MMP inhibitors is ongoing.
Delivery routes: Oral, intraperitoneal, intrapleural
How these drugs work: Matrix metalloproteinases are a family of enzymes normally secreted by connective tissue cells and inflammatory cells (phagocytes). They are called metalloproteinases because they contain a zinc atom at their catalytic (active) site. These enzymes play a role in several normal physiologic processes, including embryo implantation and normal angiogenesis associated with tissue growth and wound healing.
Malignant tumors undergo invasive growth and metastasis. The viscous connective tissue matrix, composed of collagens, laminins, fibronectins, elastins, and proteoglycans, forms the scaffolding for cellular organization in tissues and provides a barrier to cancer cell migration. Cancer cells, however, can also secrete matrix metalloproteinases, which allows metastasis to proceed by breaking down the connective tissue extracellular matrix. Matrix metalloproteinases are also important contributors to abnormal angiogenesis, the process by which cancer cells stimulate the production of new blood capillaries that deliver nutrients to the tumor cells and are essential for their continued growth.
Researchers identified compounds in tissues that inhibited the activity of the matrix metalloproteinases and have developed new inhibitors by chemical synthesis. The inverse relation between matrix metalloproteinase activity and clinical outcome in cancer has led to development and testing of these inhibitors in pancreatic, colon, and liver tumor model systems. Since 1993, matrix metalloproteinase inhibitors have undergone rapid clinical development for efficacy in treating colon, ovarian, pancreatic, prostate, gastric, skin, and non-small-cell and small-cell lung cancers. The most promising inhibitors can be administered orally, making them suitable for chronic administration, which is necessary for optimal effect.
Targeting matrix metalloproteinases in cancer is complicated because they are necessary for normal physiological processes. Thus, researchers must find a delicate balance between disease treatment and the progression of these processes. Clinical trials on synthetic broad-spectrum inhibitors (targeting several matrix metalloproteinases) have yielded disappointing results in cancer pathology. Nevertheless, researchers are making intensive efforts to find new classes of matrix metalloproteinase inhibitors with high (rather than broad) selectivity against specific metalloproteinases.
Researchers aim to utilize tissue inhibitors of metalloproteinases (TIMPs) as an alternative to small molecule inhibitors, allowing greater inhibitor selectivity. Research concerned with engineering such inhibitors focuses on three main targets—MMP-3, which induces epithelial-mesenchymal transition (EMT) and promotes lung and breast cancer progression, MMP-10 which is key in maintaining the cancer stem cell phenotype in lung cancers, and MMP-9 which facilitates the metastasis and angiogenesis of breast and other cancers.
Side effects: Reported side effects from matrix metalloproteinase inhibitors include abdominal pain, fever, elevated liver enzymes, musculoskeletal pain and stiffness, mild thrombocytopenia, skin rash, and cutaneous phototoxicity.
Bibliography
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Cabral-Pacheco, Griselda A., et al. “The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases.” International Journal of Molecular Sciences, vol. 21, no. 24, 20 Dec. 2020, doi:10.3390/ijms21249739.
Clendeninn, Neil, and Appelt Krzysztof. Matrix Metalloproteinase Inhibitors in Cancer Therapy. Humana, 2011.
Gupta, Satya Prakash. Matrix Metalloproteinase Inhibitors: Specificity of Binding and Structure-Activity Relationships. Springer, 2012.
"Proteases in Cancer: Evette S. Radisky." Mayo Clinic, www.mayo.edu/research/labs/proteases-cancer/research-projects/targeting%20matrix-metalloproteinases-using-tissue-inhibitors. Accessed 20 June 2024.
Raeeszadeh-Sarmazdeh, Maryam, et al. “Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics.” Cells, vol. 9, no. 5, 25 May 2020. doi:10.3390/cells9051313.
Said, Anan H., Jean-Pierre Raufman, and Guofeng Xie. "The Role of Matrix Metalloproteinases in Colorectal Cancer." Cancers, vol. 6, no. 1, 2014, pp. 366–75. doi:10.3390/cancers6010366.