Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies

Das, Sanjib; Amin, Sk. Abdul; Jha, Tarun

doi:10.1016/j.ejmech.2021.113623

Cited by 69 publications

(41 citation statements)

References 254 publications

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“…They included a series of aryl-sulfonamide, aryl-sulfonide, aryl sulfonyl based-glutamine, aryl carboxamide-based isoglutamine, and biphenyl-substituted lysine derivatives with affinities in the low nanomolar range. Whether these compounds are effective in clinic has not been shown to date [207][208][209][210].…”

Section: Mmp2 and Mmp9mentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.

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Section: Mmp2 and Mmp9mentioning

confidence: 99%

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Verhulst

Garnier

Meester

et al. 2022

Cancers

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“… 60 Inhibitory antibodies have shown superior selectivity and efficacy against MMPs compared with small molecules. 61 MMP-2 and MMP-14, 2 of the MMPs that we found to be consistently upregulated in AML subtypes, have already been implicated in a number of malignancies, 62,63 and for this reason, have been selected as antigens to generate a number of inhibitory antibodies. 61 Future studies should assess if selective inhibition of a certain MMP can be indicated for specific AML subtypes.…”

Section: Discussionmentioning

confidence: 95%

Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness

et al. 2022

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Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias, linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix remodeling, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness, therefore we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation, and lower AML infiltration, proliferation and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit the loss of HSPC and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

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“…After activation by hydrolysis, MMP2 can degrade gelatin and various proteins in extracellular matrix, which play an important role in the invasion and metastasis of tumors [ 39 ]. MMP2 is found to be mainly released by endothelial cells, monocytes, leukocytes, chondrocytes, platelets, osteoblasts, dermal fibroblasts and keratinocytes [ 40 ]. It has been reported that MMP2 expression in esophageal cancer is higher than the corresponding esophageal epithelium [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated ATF1 at Thr184 promotes metastasis and regulates MMP2 expression in gastric cancer

Cao

et al. 2022

J Transl Med

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Background Studies have revealed an important role of activating transcription factor 1 (ATF1) and phosphorylated ATF1 at Ser63 in tumors. Our previous study identified Thr184 as a novel phosphorylation site of ATF1. However, the role of phosphorylated ATF1 at Thr184 (p-ATF1-T184) in tumor is unclear. This study figured out the role of p-ATF1-T184 in the metastasis of gastric cancer (GC) and in the regulation of Matrix metallopeptidase 2 (MMP2). Methods Immunohistochemical analysis (IHC) was performed to analyze the level of p-ATF1-T184 and its relationship with clinicopathological characteristics. Wound scratch test, Transwell assay were used to observe the role of p-ATF1-T184 in the invasion and metastasis of GC. The regulation of MMP2 by p-ATF1-T184 was investigated by a series of experiments including quantitative RT-PCR, western blot, gelatin zymography assay, Chromatin immunoprecipitation (ChIP), luciferase reporter assay and cycloheximide experiment. The Cancer Genome Atlas (TCGA) data were used to analyze the expression and prognostic role of ATF1 and MMP2 in GC. Mass spectrometry (MS) following co-immunoprecipitation (co-IP) assay was performed to identify potential upstream kinases that would phosphorylate ATF1 at Thr184. Results High expression level of p-ATF1-T184 was found and significantly associated with lymph node metastasis and poor survival in a GC cohort of 126 patients. P-ATF1-T184 promoted migration and invasion of gastric cancer cells. Phosphorylation of ATF1-T184 could regulate the mRNA, protein expression and extracellular activity of MMP2. P-ATF1-T184 further increased the DNA binding ability, transcription activity, and stabilized the protein expression of ATF1. Moreover, TCGA data and IHC results suggested that the mRNA level of ATF1 and MMP2, and protein level of p-ATF1-T184 and MMP2 could be prognosis markers of GC. Two protein kinase related genes, LRBA and S100A8, were identified to be correlated with the expression ATF1 in GC. Conclusion Our results indicated that p-ATF1-T184 promoted metastasis of GC by regulating MMP2.

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Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies

Cited by 69 publications

References 254 publications

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness

Phosphorylated ATF1 at Thr184 promotes metastasis and regulates MMP2 expression in gastric cancer

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