Cancer matrix metalloproteinases

The hypothesis that stress can modulate MMP expression is also supported by studies in mice. Using social isolation as a stressor, the mRNA levels of MMP-2, MMP-9, matrix-type matrix metalloproteinase-1 (MT1-MMP), and urokinase-type plasminogen activator were higher in the tumor and liver tissues of the isolated mice than in control mice.91 Furthermore, a recent study has shown that restraint stress causes an increase in expression of the plasminogen activator inhibitor-1, another key player in the plas-minogen/plasmin enzyme system in mice.92 As these enzymes have been described to have functions besides their role in ECM remodeling,93 studies on stress-related effects on MMP/TIMP balance have implications in the relationship between stress and cancer initiation and progression.. 

Egeblad, M. and Werb, Z., New functions for the matrix metalloproteinases in cancer... 

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

Matrix metalloproteinases (MMPs) are a class of zinc- and calcium-dependent enzymes that are responsible for the metabolism of extracellular matrix proteins [27]. Increased activity of MMPs has been associated with pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer s disease [28-31]. Therefore, they constitute an important group of drug targets. Their inhibition is accomplished by blocking the active site of the catalytic domain with ligands that contain hydroxamic or carboxylic acids to chelate the Zn metal. The identification of low molecular weight compounds that contain different scaffolds may lead to the development of a new class of specific inhibitors. 

Trispyrazolylborates are models for tris-histidine active sites in zinc enzymes, e.g., the matrix metalloproteinases involved in breakdown of extracellular matrices. Inhibition of these metalloproteinases may prove valuable in the treatment of, inter alios, cancer and arthritis, so efforts are being made to find appropriate ligands to block the zinc active site. The search has recently moved on from hydroxamates to hydroxypyridinones - l-hydroxy-2-pyridinone is a cyclic analogue of hydroxamic acid. As reported in Section II.B.2 earlier, hydroxypyridinones form stable five-coordinate complexes on reaction with hydrotris(3,5-phenylmethylpyrazolyl)borate zinc hydroxide. Modeling studies suggest that hydroxypyridinonate ligands should be able to access the active site in the enzyme with ease (110). 

In a study conducted by Szardenings et various combinatorial libraries of DPKs scaffolds were created to design and evaluate the activity of DPKs as inhibitors of the matrix metalloproteinases, namely, collegenase-1 and gelatinase B. This study created structure-activity relationships (SAR) for side chains attached to a DPK core structure. These enzymes are therapeutic targets with indications in the treatment of cancer, arthritis, autoimmunity, and cardiovascular disease. 

Shishodia S, Majnmdar S, Banerjee S, Aggarwal BB. (2003) Ursolic acid inhibits nnclear factor-kappa B activation indnced by carcinogenic agents throngh snppression of Ikappa Balpha kinase and p65 phosphorylation Correlation with down-regnlation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin Dl. Cancer Res 63 4375 383. 

Although much has been learned ftom in vitro assays, we do not yet fully understand the predominant migratory mechanisms used by cancer cells in vivo. It is important that any molecular mediators (or their inhibitors) identified in one assay are tested in complementary assays and validated in appropriate in vivo models before they can be assumed to play a significant role in invasion and metastasis. There are several examples where a molecule can have either positive or negative regulatory roles in key cellular functions depending on the cellular/microenvironmental context (e.g., tissue inhibitors of matrix metalloproteinases TIMPs (12)). Thus, care needs to be taken to avoid undesirable activities or, as in the example of some angiogenic inhibitors, compensatory mechanisms that result in adverse events (13). 

Chung, C. H. and Hu, M. L. (2008). L-Carnosine inhibits metastasis of SK-Hep-1 cells by inhibition of matrix metalloproteinase-9 expression and induction of an antimetastatic gene, nm23-Hl. Nutr. Cancer 60, 526-533. 

Maximizing the Therapeutic Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Cancer... 

Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997 89 1260-1270. 

Moore MJ, Hamm P, Eisenberg P, Dagenais M, Hagan K, Fields A, et al. A comparison between gemcitabine (GEM) and the matrix metalloproteinase (MMP) inhibitor BAY 12-9566 (9566) inpatients (pts) with advanced pancreatic cancer. ProcAm Soc Clin Oncol 2000 19 240a (abstract). 

Wojtowicz PS, TorriJ, Johnson M, Steen V, Marshall J, Ness E, etal. Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 1998 16 2150-2156. 

Tumor Models in Cancer Research, edited by Beverly A. Teicher, 2002 Tumor Suppressor Genes in Human Cancer, edited by David E. Fisher, 2001 Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and Krzysztof Appelt, 2001... 

S. Furumoto, R. Iwata, T. Ido, Design and synthesis of fluorine-18 labeled matrix metalloproteinase inhibitors for cancer imaging, J. Label. Compd. Radiopharm. 45 (2002) 975-986. 

Ho YC, Yang SF, Peng CY, Chou MY, Chang YC. 2007. Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells and decreases the productions of matrix metalloproteinases and urokinase-plasminogen activator. J Oral Pathol Med 36 588-593. 

Tang FY, Chiang EP, Sun YC. 2008. Resveratrol inhibits heregulin-betal-mediated matrix metalloproteinase-9 expression and cell invasion in human breast cancer cells. J Nutr Biochem 19 287-294. 

Su CC, Chen GW, Lin JG, Wu LT, Chung JG. 2006. Curcumin inhibits cell migration of human colon cancer colo 205 cells through the inhibition of nuclear factor kappa B/p65 and down-regulates cyclooxygenase-2 and matrix metalloproteinase-2 expressions. Anticancer Res 26 1281-1288. 

AD Baxter, JB Bird, R Bannister, R Bhogal, DT Manallack, RW Watson, DA Owen, J Montana, J Henshilwood, RC Jackson. Matrix metalloproteinase inhibitors in cancer therapy. Totawa, NJ Humana Press, 2000, pp 193-222. 

Originally developed as part of a large-scale effort headed by the United States National Cancer Institute to investigate chemotherapeutic agents from natural sources, paclitaxel was approved by the FDA in 1992 as an antineoplastic agent to treat metastatic ovarian cancer after failure of first-line or subsequent chemotherapy (37). Further studies demonstrated efficacy in other solid tumors (38). In addition, paclitaxel was shown to inhibit T- and B-cell proliferation when tested for transplant-rejection application (39,40) and has demonstrated inhibition of matrix-metalloproteinase synthesis in studies conducted to test its utility for rheumatoid arthritis (41). 

Hidalgo M, Eckhardt SG, Development of matrix metalloproteinase inhibitors in cancer therapy, J Natl Cancer Inst, 2001 93(3) 178-193. 

Vihinen P, Kahari VM (2002) Matrix metalloproteinases in cancer prognostic markers and therapeutic targets. Int J Cancer 99 157-166... 

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