-
Turkish Neurosurgery 2023To investigate the efficacy of locally applied batimastat after laminectomy in preventing postoperative epidural fibrosis.
AIM
To investigate the efficacy of locally applied batimastat after laminectomy in preventing postoperative epidural fibrosis.
MATERIAL AND METHODS
Thirty-two Wistar albino male rats weighing 200?250 g were used. The rats were assigned to four different groups (I-Control group, II-sham group, III-Laminectomy+Batimastat group, and IV-Laminectomy+SpongostanTM group). The rats were euthanized 28 days after surgery before TNF-?, IL6, IL-1?, IL10, TGF-?1, and MMP9 gene expression levels of tissue in the surgical area were determined with qPCR. TNF-?, IL6, and IL10 protein levels were also measured in both tissue and plasma. In addition, the surgical area was evaluated by histopathological and immunohistochemical methods.
RESULTS
TNF-?, IL6, and IL-1? gene expression levels were higher in the batimastat group than in the control group. Whereas IL10 gene expression levels increased about two-fold in the sham and SpongostanTM groups, in the batimastat group, it was similar to that in the control group. TGF-?1 gene expression was three-fold higher in the sham group but was similar to that in the control group in both batimastat and SpongostanTM groups. MMP9 gene expression levels significantly decreased only in the batimastat group. In addition, fibrosis score, fibroblast cell count, inflammatory cell count, and CD105 expression decreased in the batimastat group relative to the control.
CONCLUSION
Molecular and pathological examination results suggested that batimastat is an effective agent in reducing the occurrence of epidural fibrosis after laminectomy.
Topics: Animals; Rats; Epidural Space; Fibrosis; Interleukin-1; Interleukin-10; Interleukin-6; Laminectomy; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Rats, Wistar
PubMed: 36482856
DOI: 10.5137/1019-5149.JTN.41841-22.2 -
Cell Biochemistry and Biophysics Sep 2014Hepatocellular carcinoma (HCC) is a malignant tumor characterized by easy metastasis and frequent recurrence. Transarterial chemoembolization (TACE) remains the routine...
Hepatocellular carcinoma (HCC) is a malignant tumor characterized by easy metastasis and frequent recurrence. Transarterial chemoembolization (TACE) remains the routine treatment for patients with HCC who are not eligible for surgical resection or percutaneous tumor ablation; however, 5-year survival rates following interventional therapy are only 17-38.8 %, with liver recurrence due to incomplete embolization and tumor angiogenesis being a significant reason for treatment failure. Ischemia and hypoxia induced by TACE is correlated with an increased expression of angiogenic factor and stimulates an increase in angiogenesis, including endothelial cells (ECs) proliferation. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic endopeptidases involved in tumor angiogenesis. In addition, MMPs stimulate tumor cell growth, migration and invasion, and metastasis. Hypoxia enhanced EC migration in a MMP-2-dependent manner while MMP inhibitors (MMPIs) significantly decreased the number of migrating cells in hypoxic cultures. We hypothesize batimastat (synthetic MMPI) nanoparticles associated with TACE could decrease HCC recurrence and metastasis. At first, batimastat nanoparticles were made from batimastat and poly(lactic-co-glycolic acid). Then, nanoparticles were mixed with lipiodol and chemotherapeutic drugs solution. The mixture was infused super-selectively into supplied artery of HCC through catheter. The disseminated area of batimastat might be same with TACE-induced hypoxia area. In the hypoxia area, batimastat inhibited the activity of MMPs, weakened the angiogenesis of tumor vascular system and migration of HCC cells. HCC cells could not escape from hypoxia area and tumor angiogenesis inhibited could not supply sufficient nutrients and O2 to residual HCC cells. With the help of batimastat, the killing effect of chemotherapeutic drugs might be enhanced. The rate of complete necrosis of HCC lesion might be increased and local recurrence and metastasis of HCC might be reduced. The hypothesis might increase the clinical efficacy of TACE and improve the prognosis of HCC patients.
Topics: Carcinoma, Hepatocellular; Catheters; Chemoembolization, Therapeutic; Combined Modality Therapy; Humans; Liver Neoplasms; Nanoparticles; Phenylalanine; Recurrence; Thiophenes
PubMed: 24639109
DOI: 10.1007/s12013-014-9893-8 -
International Journal of Molecular... Apr 2024The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is...
The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.
Topics: Humans; Apoptosis; Hematologic Neoplasms; Cell Line, Tumor; Cell Survival; Antineoplastic Agents; Cytostatic Agents; Cell Proliferation; Hydroxamic Acids; HL-60 Cells; Matrix Metalloproteinase Inhibitors; Cell Cycle Checkpoints; MAP Kinase Signaling System; Leukemia, Myeloid, Acute; Phenylalanine; Thiophenes
PubMed: 38674139
DOI: 10.3390/ijms25084554 -
Pharmacology & Therapeutics 1997Matrix metalloproteinases (MMPs) are a homologous family of enzymes that are involved in tissue remodeling and morphogenesis. Collectively, these enzymes are capable of... (Review)
Review
Matrix metalloproteinases (MMPs) are a homologous family of enzymes that are involved in tissue remodeling and morphogenesis. Collectively, these enzymes are capable of degrading all components of the extracellular matrix, and they play an important role in normal physiologic conditions, such as wound healing and other processes involving tissue remodeling. However, increased activity of these enzymes now has been observed in a number of different pathological conditions, and it has been hypothesized that such increased activity of MMPs might play a role in the pathogenesis of these conditions. Cancer is one such condition; extracellular matrices constitute the principal barrier to tumor growth and spread, and there is growing experimental evidence that malignant tumors utilize MMPs to overcome these barriers. Consequently, inhibitors of MMPs represent an attractive target for a new class of anticancer agents. Marimastat and batimastat are potent broad-spectrum inhibitors of all major MMPs and have been shown to prevent or reduce spread and growth of a number of different malignant tumors in numerous animal models. Both agents are now in advanced clinical testing in a number of different solid tumors in North America and Europe. The purpose of this paper is to review available preclinical and emerging clinical data, using batimastat and marimastat as prototype MMP inhibitors in the cancer area.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Colorectal Neoplasms; Enzyme Inhibitors; Female; Hemangioma; Humans; Hydroxamic Acids; Melanoma; Metalloendopeptidases; Mice; Ovarian Neoplasms; Pancreatic Neoplasms; Phenylalanine; Protease Inhibitors; Skin Neoplasms; Thiophenes
PubMed: 9364582
DOI: 10.1016/s0163-7258(97)00023-5 -
International Immunopharmacology Nov 2003In this study, we report evidences that Mycobacterium tuberculosis (MTB)-induced apoptosis in macrophages is reduced by a broad-spectrum hydroxamic acid-based matrix...
In this study, we report evidences that Mycobacterium tuberculosis (MTB)-induced apoptosis in macrophages is reduced by a broad-spectrum hydroxamic acid-based matrix metalloproteinase (MMP) inhibitor, Batimastat (BB-94). In particular, we show that BB-94 administration to MTB-infected macrophages inhibits apoptosis and the downmodulation of membrane CD14 expression. Moreover, the addition of broad spectrum matrix metalloproteinase inhibitor to cell culture, during MTB infection, decreases the release of soluble TNF-alpha and leads to a simultaneous increase of membrane TNF-alpha. These results show that MTB-induced apoptosis in macrophages is reduced by a MMP inhibitor and most probably is related to TNF-alpha release. This identifies BB-94 as a simultaneous anti-apoptotic and anti-inflammatory molecule during MTB infection.
Topics: Annexin A5; Apoptosis; Cells, Cultured; Flow Cytometry; HLA-DR Antigens; Humans; Interleukin-6; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Macrophages; Mycobacterium tuberculosis; Phenylalanine; Propidium; Thiophenes; Tumor Necrosis Factor-alpha
PubMed: 14555290
DOI: 10.1016/S1567-5769(03)00202-9 -
ACS Chemical Neuroscience Jan 2016The ADAM family of metalloproteases cleave a diverse range of transmembrane substrates, resulting in the release of their soluble ectodomains. This process of protein...
The ADAM family of metalloproteases cleave a diverse range of transmembrane substrates, resulting in the release of their soluble ectodomains. This process of protein shedding, termed α-secretase processing, is involved in many facets of both normal and disease related cellular function. While the processing of substrates has been well documented, the regulation and trafficking of the ADAMs are less well understood. Tools that allow for the study of ADAMs under their native environment will allow for a better understanding of their regulation and activity. Here we describe the design and evaluation of a novel fluorescent analogue of a well-characterized ADAM inhibitor, Batimastat. This probe exhibited similar activity for inhibiting α-secretase processing in cells as did Batimastat. Importantly, this probe specifically labeled ADAMs fluorescently in both fixed and living cells, enabling the possibility to study the trafficking of α-secretase proteins in a dynamic environment.
Topics: ADAM Proteins; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Membrane Glycoproteins; Microscopy, Fluorescence; Phenylalanine; Protease Inhibitors; RNA, Small Interfering; Thiophenes; Transfection
PubMed: 26559179
DOI: 10.1021/acschemneuro.5b00283 -
Drugs in R&D Feb 1999
Topics: Animals; Antineoplastic Agents; Ascites; Drugs, Investigational; Humans; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Neoplasms; Phenylalanine; Pleural Effusion, Malignant; Protease Inhibitors; Thiophenes
PubMed: 10566008
DOI: 10.2165/00126839-199901020-00005 -
Journal of the National Cancer Institute Oct 1995Matrix metalloproteinases (MMPs) are involved in the invasion and metastasis of human cancers by mediating the degradation of extracellular matrix components. Therefore,...
BACKGROUND
Matrix metalloproteinases (MMPs) are involved in the invasion and metastasis of human cancers by mediating the degradation of extracellular matrix components. Therefore, these enzymes constitute promising targets in the development of anticancer therapies. Batimastat ([(4-N-hydroxyamino)-2R-isobutyl-3S-(thienyl-thiomethyl)succinyl]-L- phenyl-alanine-N-methylamide) is one of a new class of agents designed to inhibit MMP activity.
PURPOSE
We asked whether batimastat, given as adjuvant therapy after primary tumor resection, could inhibit local-regional tumor regrowth and the formation of lung metastases in a human breast cancer xenograft model. We also explored possible effects of batimastat on breast cancer cell viability and on the accumulation of specific messenger RNAs (mRNAs).
METHODS
Human MDA-MB-435 breast cancer cells were treated in vitro for 6 days with batimastat at concentrations ranging from 0.1 to 10.0 microM, and then viable cell counts were performed. The activity of collagenases, directly associated with cultured MDA-MB-435 cells or released into their culture fluids, was assessed by gelatin zymography after 1 and 3 days of batimastat treatment (drug range, 0.2-2.0 microM). Athymic nude mice were given daily intraperitoneal injections of batimastat (30 mg/kg body weight) after resection of MDA-MB-435 primary tumors grown in their mammary fat pads; the volumes of tumor regrowths and the numbers and volumes of lung metastases were calculated; neovascularization in the regrowths was assessed by immunohistochemical analysis with an antibody directed against CD31, an endothelial cell antigen. The effect of batimastat treatment on the accumulation of mRNAs encoding specific MMPs and the tissue inhibitor of metalloproteinases-2 (TIMP-2) in cultured cells, primary tumors, and tumor regrowths was measured by RNA dot blotting and hybridization with complementary probes. Linear regression analysis, Student's t tests, and chi-squared analysis were used to evaluate the data.
RESULTS
The viability of cultured MDA-MB-435 cells was not affected by treatment with batimastat; however, measured activities for the 72-kd and 92-kd collagenases released by these cells were reduced after batimastat treatment. Intraperitoneal injection of batimastat significantly inhibited the local-regional regrowth of resected MDA-MB-435 tumors in athymic nude mice (in comparison with control mice, P = .035), and it reduced the incidence (P < .05), number (P = .0001), and total volume (P = .0001) of lung metastases. Batimastat treatment did not affect cellular levels of MMP or TIMP-2 mRNAs.
CONCLUSION
Batimastat inhibits human breast cancer regrowth and metastasis in a nude mouse xenograft model. Potential mechanisms for batimastat's inhibitory activity do not include direct cell toxicity or alteration of MMP or TIMP mRNA levels.
Topics: Animals; Breast Neoplasms; Chemotherapy, Adjuvant; Chi-Square Distribution; Collagenases; Female; Humans; Linear Models; Lung Neoplasms; Metalloendopeptidases; Mice; Mice, Nude; Neoplasm Recurrence, Local; Neoplasm Transplantation; Phenylalanine; RNA, Messenger; RNA, Neoplasm; Thiophenes; Tumor Cells, Cultured
PubMed: 7563189
DOI: 10.1093/jnci/87.20.1546 -
Proceedings of the National Academy of... Apr 1996Matrix metalloproteinase enzymes have been implicated in degenerative processes like tumor cell invasion, metastasis, and arthritis. Specific metalloproteinase...
Matrix metalloproteinase enzymes have been implicated in degenerative processes like tumor cell invasion, metastasis, and arthritis. Specific metalloproteinase inhibitors have been used to block tumor cell proliferation. We have examined the interaction of batimastat (BB-94) with a metalloproteinase [atrolysin C (Ht-d), EC 3.4.24.42] active site at 2.0-angstroms resolution (R = 16.8%). The title structure exhibits an unexpected binding geometry, with the thiophene ring deeply inserted into the primary specificity site. This unprecedented binding geometry dramatizes the significance of the cavernous primary specificity site, pointing the way for the design of a new generation of potential antitumor drugs.
Topics: Amino Acid Sequence; Binding Sites; Computer Simulation; Conserved Sequence; Crystallography, X-Ray; Fourier Analysis; Metalloendopeptidases; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Phenylalanine; Protease Inhibitors; Protein Structure, Secondary; Thiophenes
PubMed: 8610113
DOI: 10.1073/pnas.93.7.2749 -
Toxins May 2020Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical...
Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a Group I (PI) metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, . Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity is completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 μM, while it is partially potentiated by calcium chloride. Molecular docking studies have demonstrated that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, Group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites.
Topics: Animals; Antineoplastic Agents; Antivenins; Binding Sites; Blood Platelets; Catalytic Domain; Collagen; Crotalid Venoms; Crotalus; Drug Repositioning; Erythrocytes; Fibrin; Fibrinolysis; Hemolysis; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Docking Simulation; Phenylalanine; Protein Binding; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Thiophenes
PubMed: 32397419
DOI: 10.3390/toxins12050309