The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination

Marusak, Charles; Bayles, Ian; Ma, Jun; Gooyit, Major; Gao, Ming; Chang, Mayland; Bedogni, Barbara

doi:10.1016/j.phrs.2016.09.033

Cited by 33 publications

(28 citation statements)

References 29 publications

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“…For instance, specific inhibition of either MMP-2 or MT1-MMP by specific shRNAs hampers melanoma cell migration and invasion. 63 Gene therapy has shown some success in animal models, and with the design of efficient and safe gene delivery into target tissues downregulation of MMPs using siRNA or overexpression of TIMPs may have clinical applications. 64 …”

Section: Other Biological and Pleiotropic Inhibitors Of Mmpsmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Liu

Khalil

2017

Progress in Molecular Biology and Translational Science

120

161

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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 post-receptor 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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Section: Other Biological and Pleiotropic Inhibitors Of Mmpsmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Liu

Khalil

2017

Progress in Molecular Biology and Translational Science

120

161

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“…And knockdown of RGS4 activated melanoma cell migration and invasion; also degradation of RGS4 increased the expression of MMPs. In addition, it has been validated that MMP2 and MMP9 are implicated in the development and metastasis of cutaneous melanoma [ 44 , 45 ]. Several evidences indicated that CXCR4/SDF1 promoted prostate cancer cell invasion through MMP9 activation [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Regulator of G protein signaling 4 inhibits human melanoma cells proliferation and invasion through the PI3K/AKT signaling pathway

et al. 2017

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Melanoma is a tumor produced by skin melanocytes, which has a high metastatic rate and poor prognosis. So far, plenty of work has been done on melanoma, but mechanisms underlying melanoma development have not been fully elucidated. Here we identified regulator of G protein signaling 4(RGS4) as novel therapeutic target for malignant melanoma and its regulating effect on melanoma. We found that endogenous RGS4 expression was much lower in melanoma tissues and cells. In A375 cell line with low endogenous RGS4 expression, the function of RGS4 was detected by up-regulation its expression with pcDNA3.1-RGS4 and knockdown its expression with siRNA. Our results showed that RGS4 could significantly reduce the proliferation, migration and invasion of melanoma cells. RGS4 is an important regulator for the apoptosis of melanocyte, and the apoptosis rate is significantly decreased in low RGS4 enviroment. RGS4 induced non-activation of PI3K/AKT pathway, resulting in decreased expression of E2F1 and Cyclin D1, thus constraining cell proliferation and invasion. These results were further confirmed in M14 cell lines. Collectively, our findings show that RGS4 plays an important role in multiple cellular functions of melanoma development and is valuable to be a therapeutic target.

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“…Thus, MT-MMPs and MMP-2 cooperate in the invasive and metastatic process of melanoma cells [123]. Recent research also showed that effective inhibition of MT1-MMP and MMP2 can effectively reduce melanoma cell growth, migration and invasion in vitro [148]. in primary melanoma patients who received adjuvant immunotherapy.…”

Section: Mt-mmpsmentioning

confidence: 99%

Skin Ageing and Cancer

Zhang¹,

Wang²,

Wang³

2017

The Role of Matrix Metalloproteinase in Human Body Pathologies

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Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn 2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Based on their structure and substrate specificity, they can be categorized into five main subgroups, namely (1) collagenases (MMP-1, MMP-8 and MMP-13); (2) gelatinases (MMP-2 and MMP-9); (3) stromelysins (MMP-3, MMP-10 and MMP-11); (4) matrilysins (MMP-7 and MMP-26) and (5) membrane-type (MT) MMPs (MMP-14, MMP-15, MMP-16, MMP-17, MMP-24 and MMP-25). MMPs can act on extracellular matrix (ECM) and non-ECM components affecting degradation and modulation of the ECM, growth-factor activation and cell-cell and cell-matrix signalling. In skin, MMPs are secreted by different cell types such as fibroblasts, keratinocytes, macrophages, endothelial cells, mast cells, and eosinophils. This chapter reviews the role of MMPs in maintaining skin homeostasis, skin ageing and skin cancer.

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The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination

Cited by 33 publications

References 29 publications

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Regulator of G protein signaling 4 inhibits human melanoma cells proliferation and invasion through the PI3K/AKT signaling pathway

Skin Ageing and Cancer

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