Best matches for glioma, matrix metalloproteinases:
The role of microglia and matrix metalloproteinases involvement in neuroinflammation and gliomas.
Könnecke H et al. Clin Dev Immunol.
(2013)
Levels of vascular endothelial growth factor and matrix metalloproteinase-9 proteins in patients with glioma.
Ma C et al. J Int Med Res.
(2014)
1.
Blaes
J, Thomé CM, Pfenning PN, Rübmann P, Sahm F, Wick A, Bunse T, Schmenger
T, Sykora J, von Deimling A, Wiestler B, Merz C, Jugold M, Haberkorn U,
Abdollahi A, Debus J, Gieffers C, Kunz C, Bendszus M, Kluge M, Platten
M, Fricke H, Wick W, Lemke D.
Mol Cancer Res. 2018 Feb 16. pii: molcanres.0563.2017. doi: 10.1158/1541-7786.MCR-17-0563. [Epub ahead of print]
IMPLICATIONS:
APG101 (asunercept) successfully used in a controlled phase II glioblastoma trial (NCT01071837) acts anti-invasively by inhibiting matrix metalloproteinase signaling resulting in additive effects together with radiotherapy and helping to further develop a treatment for this devastating disease.
Copyright ©2018, American Association for Cancer Research.
2.
Marín-Ramos NI, Thein TZ, Cho HY, Swenson SD, Wang W, Schönthal AH, Chen TC, Hofman FM.
Mol Cancer Ther. 2018 Feb 13. pii: molcanther.0591.2017. doi: 10.1158/1535-7163.MCT-17-0591. [Epub ahead of print]
Glioblastoma multiforme is a malignant brain tumor noted for its
extensive vascularity, aggressiveness, and highly invasive nature,
suggesting that cell migration plays an important role in tumor
progression. The poor prognosis in GBM is associated with a high rate of
tumor recurrence, and resistance to the standard of care chemotherapy,
temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and
perillyl alcohol (POH), has proven to be 10 fold more cytotoxic to glioma
stem cells (GSCs) than TMZ, and is active against TMZ-resistant tumor
cells. In this study, we show that NEO212 decreases migration and
invasion of primary cultures of patient-derived GSCs, in both
mesenchymal USC02 and proneural USC04 populations. The mechanism by
which NEO212 reduces migration and invasion appears to be independent of
its DNA alkylating effects, which cause cytotoxicity during the first
hours of treatment, and is associated with a decrease in the FAK/Src
signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases
the production of matrix metalloproteinases
MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of
epithelial and mesenchymal markers suggests that NEO212 increases the
expression of epithelial-like characteristics, suggesting a reversion of
the epithelial-to-mesenchymal transition (EMT) process. Furthermore, in
an in vivo orthotopic glioma
model, NEO212 decreases tumor progression by reducing invasion of GSCs,
thereby increasing survival time of mice. These studies indicate that
NEO212, in addition to cytotoxicity, can effectively reduce migration
and invasion in GSCs, thus exhibiting significant clinical value in the
reduction of invasion and malignant glioma progression.
3.
Liu X, Su P, Meng S, Aschner M, Cao Y, Luo W, Zheng G, Liu M.
Int J Biol Sci. 2017 Oct 31;13(11):1351-1360. doi: 10.7150/ijbs.20670. eCollection 2017.
4.
Yu CF, Chen FH, Lu MH, Hong JH, Chiang CS.
Br J Cancer. 2017 Dec 5;117(12):1828-1836. doi: 10.1038/bjc.2017.362. Epub 2017 Oct 24.
This study illustrated that tumour-derived MMP2 has at least two roles
in tumour malignancy; to enhance tumour invasiveness by degrading the
extracellular matrix and to enhance tumour growth by promoting vessel maturation and function.Free PMC Article
5.
Qu M, Yu J, Liu H, Ren Y, Ma C, Bu X, Lan Q.
Mol Cells. 2017 Oct;40(10):761-772. doi: 10.14348/molcells.2017.0104. Epub 2017 Oct 17.
Glioblastoma is the most frequent and most aggressive brain tumor in
adults. Solute carrier family 8 member 2 (SLC8A2) is only expressed in
normal brain, but not present in other human normal tissues or in
gliomas. Therefore, we hypothesized that SLC8A2 might be a glioma
tumor suppressor gene and detected the role of SLC8A2 in glioblastoma
and explored the underlying molecular mechanism. The glioblastoma U87MG
cells stably transfected with the lentivirus plasmid containg SLC8A2
(U87MG-SLC8A2) and negative control (U87MG-NC) were constructed. In the
present study, we found that the tumorigenicity of U87MG in nude mice
was totally inhibited by SLC8A2. Overexpression of SLC8A2 had no effect
on cell proliferation or cell cycle, but impaired the invasion and
migration of U87MG cells, most likely through inactivating the
extracellular signal-related kinases (ERK)1/2 signaling pathway,
inhibiting the nuclear translocation and DNA binding activity of nuclear
factor kappa B (NF-κB), reducing the level of matrix metalloproteinases
(MMPs) and urokinase-type plasminogen activator (uPA)-its receptor
(uPAR) system (ERK1/2-NF-κB-MMPs/uPA-uPAR), and altering the protein
levels of epithelial to mesenchymal transitions (EMT)-associated
proteins E-cardherin, vimentin and Snail. In addition, SLC8A2 inhibited
the angiogenesis of U87MG cells, probably through combined inhibition of
endothelium-dependent and endothelium-nondependent angiogenesis
(vascular mimicry pattern). Totally, SLC8A2 serves as a tumor suppressor
gene and inhibits invasion, angiogenesis and growth of glioblastoma.Free PMC Article
6.
Zhang C, Wang L, Chen J, Liang J, Xu Y, Li Z, Chen F, Du D.
Biomed Pharmacother. 2017 Dec;96:596-602. doi: 10.1016/j.biopha.2017.10.031. Epub 2017 Oct 13.
- The mammalian diaphanous-related formin 1 (Diaph1) which belongs to formin-homology protein family, is a target of RhoA and involved in a number of actin-related biological processes, which abnormally expressed in pathological conditions in a number of tumors. Immunohistochemical analysis showed that Diaph1 was overexpressed in glioma tissues compared with normal human brain tissue. Diaph1 gene silencing RNA interference (RNAi) significantly inhibited the migratory activity of human glioma cell lines U87 and U251. Moreover, data obtained from qRT-PCR and Western-blot analysis showed that the mRNA and protein expression of matrix metalloproteinase2 and 9 (MMP2 and MMP9) was significantly suppressed in these Diaph1 knockdown cell lines, as well as gelatin zymography analysis revealed that the activity of MMP2 and MMP9 in conditioned medium was markedly decreased. In conclusion, our data demonstrate that Diaph1 is highly expressed in human glioma, plays a significant role in glioma cell migration, and can influence the expression and activity of MMP2 and MMP9 indirectly in human glioma cell lines U87 and U251. We provide a theoretical basis for further experimental studies and Diaph1 using on glioma therapy.
7.
Chen Y, Zhang M, Jin H, Li D, Xu F, Wu A, Wang J, Huang Y.
Theranostics. 2017 Aug 15;7(14):3489-3503. doi: 10.7150/thno.20578. eCollection 2017.
Malignant glioma
is one of the most untreatable cancers because of the formidable
blood-brain barrier (BBB), through which few therapeutics can penetrate
and reach the tumors. Biologics have been booming in cancer therapy in
the past two decades, but their application in brain tumor has long been
ignored due to the impermeable nature of BBB against effective delivery
of biologics. Indeed, it is a long unsolved problem for brain delivery
of macromolecular drugs, which becomes the Holy Grail in medical and
pharmaceutical sciences. Even assisting by targeting ligands, protein
brain delivery still remains challenging because of the synthesis
difficulties of ligand-modified proteins. Herein, we propose a
rocket-like, multistage booster delivery system of a protein toxin,
trichosanthin (TCS), for antiglioma treatment. TCS is a
ribosome-inactivating protein with the potent activity against various
solid tumors but lack of specific action and cell penetration ability.
To overcome the challenge of its poor druggability and site-specific
modification, intein-mediated ligation was applied, by which a
gelatinase-cleavable peptide and cell-penetrating peptide (CPP)-fused
recombinant TCS toxin can be site-specifically conjugated to lactoferrin
(LF), thus constructing a BBB-penetrating, gelatinase-activatable
cell-penetrating nanohybrid TCS toxin. This nanohybrid TCS system is
featured by the multistage booster strategy for glioma
dual-targeting delivery. First, LF can target to the BBB-overexpressing
low-density lipoprotein receptor-related protein-1 (LRP-1), and assist
with BBB penetration. Second, once reaching the tumor site, the
gelatinase-cleavable peptide acts as a separator responsive to the glioma-associated matrix metalloproteinases
(MMPs), thus releasing to the CPP-fused toxin. Third, CPP mediates
intratumoral and intracellular penetration of TCS toxin, thereby
enhancing its antitumor activity. The BBB penetration and
MMP-2-activability of this delivery system were demonstrated. The
antiglioma activity was evaluated in the subcutaneous and orthotopic
animal models. Our work provides a useful protocol for improving the
druggability of such class of protein toxins and promoting their in-vivo application for targeted cancer therapy.Free PMC Article
8.
Yu Y, Fu X, Ran Q, Yang K, Wen Y, Li H, Wang F.
Biochimie. 2017 Nov;142:144-151. doi: 10.1016/j.biochi.2017.09.005. Epub 2017 Sep 11.
. In the present study we determined the anticancer potential of globularifolin against human glioma U87 cell line and human astrocytes. The results showed that globularifolin exhibits an IC50 value of 7.5 μM against glioma U87 cells as against the IC50
of 65 μM against human astrocytes. The molecule exerted its anticancer
activity through induction of apoptosis as evident from the Bid-, and
Bax controlled cytochrome c and Omi/HtrA2 release, XIAP suppression, and
caspase-9 and 3 signalling cascade. Additionally, it also caused cell
cycle arrest of human glioma
U87 cancer cells in the S phase of the cell cycle. Interestingly,
globularifolin also caused significant inhibition of Akt/mTOR/p70S6K and
MEK/ERK pathways. Globularifolin also inhibits cell migration and
invasion by regulating the expression of matrix metalloproteinases (MMPs) in U87 glioma cells. We further investigated whether globularifolin exhibits the same effectiveness against glioma
cell xenografts in nude mice in vivo and it was observed that
globularifolin significantly reduced the tumor growth and volume in vivo
indicating the potential of globularifolin as lead molecule for glioma chemotherapy.
9.
Zheng Y, Miu Y, Yang X, Yang X, Zhu M.
DNA Cell Biol. 2017 Oct;36(10):853-861. doi: 10.1089/dna.2017.3818. Epub 2017 Aug 17.
Chemokine receptor 7 (CCR7) has emerged as an inducer of invasion,
migration, and epithelial-mesenchymal transition (EMT) in cancer. In
this research, human malignant glioma
cells were stimulated with transforming growth factor beta 1 (TGF-β1)
and siCCR7. The data show that CCR7 mediates TGF-β1-induced EMT,
migration, and invasion in U251 and U87 cells and that these effects of
TGF-β1 were reversed by treatment with siCCR7 or a CCR7 neutralizing
antibody. Importantly, the TGF-β1-mediated increase in nuclear factor
kappaB (NF-κB) activity in human glioma
cells was reduced by treatment with siCCR7 or a CCR7 neutralizing
antibody. Furthermore, CCR7 was shown to mediate TGF-β1-induced glioma cancer cell migration by activating matrix
metalloproteinase 2 (MMP2)/9. Our results indicate that CCR7 mediates
TGF-β1-induced MMP2/9 expression through NF-κB signaling, thus
facilitating glioma
cell migration, invasion, and EMT, all of which progressively increase
with glioblastoma progression. These findings indicate that CCR7 is a
potential therapeutic target for malignant glioma.
10.
Qin W, Rong X, Dong J, Yu C, Yang J.
Oncol Rep. 2017 Sep;38(3):1543-1550. doi: 10.3892/or.2017.5816. Epub 2017 Jul 13.
11.
Özdemir A, Sever B, Altıntop MD, Temel HE, Atlı Ö, Baysal M, Demirci F.
Molecules. 2017 Jul 4;22(7). pii: E1109. doi: 10.3390/molecules22071109.
Matrix metalloproteinases
(MMPs) are important proteases involved in tumor progression including
angiogenesis, tissue invasion, and migration. Therefore, MMPs have been
reported as potential diagnostic and prognostic biomarkers in many types
of cancer. New oxadiazole, thiadiazole, and triazole derivatives were
synthesized and evaluated for their anticancer effects on A549 human
lung adenocarcinoma and C6 rat glioma
cell lines. In order to examine the relationship between their
anticancer activity and MMP-9, the compounds were evaluated for their
inhibitory effects on MMPs. N-(1,3-Benzodioxol-5-ylmethyl)-2-{[5,[5-(((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl)-1,3,4-oxadiazol-2-yl]thio}acetamide (8) and N-(1,3-benzodioxol-5-ylmethyl)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetamide (9)
revealed promising cytotoxic effects on A549 and C6 cell lines similar
to cisplatin without causing any toxicity towards NIH/3T3 mouse
embryonic fibroblast cell line. Compounds 8 and 9 were also the most effective MMP-9 inhibitors in this series. Moreover, docking studies pointed out that compounds 8 and 9
had good affinity to the active site of the MMP-9 enzyme. The molecular
docking and in vitro studies suggest that the MMP-9 inhibitory effects
of compounds 8 and 9 may play an important role in lung adenocarcinoma and glioma treatmentFree Article
12.
Armento A, Ilina EI, Kaoma T, Muller A, Vallar L, Niclou SP, Krüger MA, Mittelbronn M, Naumann U.
Int J Oncol. 2017 Aug;51(2):702-714. doi: 10.3892/ijo.2017.4051. Epub 2017 Jun 21.
Glioblastoma (GBM), the most frequent and aggressive malignant primary
brain tumor, is characterized by a highly invasive growth. In our
previous study we showed that overexpression of Carboxypeptidase E (CPE)
mitigated glioma
cell migration. In the present study we aimed at deciphering the
regulatory mechanisms of the secreted form of CPE (sCPE). By
transcriptome analysis and inhibition of signaling pathways involved in
the regulation of cell growth and motility, we discovered that
overexpression of sCPE was accompanied by differential regulation of
mRNAs connected to the motility-associated networks, among others FAK,
PAK, Cdc42, integrin, STAT3 as well as TGF-β. Especially SLUG was
downregulated in sCPE-overexpressing glioma cells, paralleled by reduced expression of matrix-metalloproteinases
(MMP) and, in consequence, by decreased cell migration. Expression of
SLUG was regulated by ERK since inhibition of ERK reverted sCPE-mediated
SLUG downregulation and enhanced cell motility. In a mouse glioma
model, overexpression of sCPE significantly prolonged survival. Our
results implicate a novel role for sCPE that mainly affects the
expression of motility-associated genes via several signal pathways.
13.
Ramezani S, Vousooghi N, Ramezani Kapourchali F, Joghataei MT.
Apoptosis. 2017 Aug;22(8):1025-1034. doi: 10.1007/s10495-017-1382-2.
- Bevacizumab (BVZ) as an antiangiogenesis therapy leads to a transient therapeutic efficacy in high-grade glioma. However, the proapoptotic potential of BVZ has not been well elucidated, yet. There is also a tumor resistance to BVZ that is linked to post-treatment metalloproteinases and AKT activities. Herein, the association between therapeutic efficacy and putative proapoptotic activity of low-dose BVZ either alone or in combination with a specific inhibitor of AKT called perifosine (PRF), in a glioma model was investigated. BALB/c mice bearing C6 glioma tumor were treated with BVZ and PRF either alone or combined for 13 days (n = 11/group). At the end of treatments, apoptosis, proliferation and vascular density, in the xenografts (3/group) were detected by TUNEL staining, Ki67 and CD31 markers, respectively. Relative levels of cleaved-caspase3, phospho-AKT (Ser473) and matrix metalloproteinase2 (MMP2) were measured using western blotting. PRF and BVZ separately slowed down tumor growth along with the cell apoptosis induction associated with a profound increase in caspase3 activity through an AKT inhibition-related pathway for PRF but not BVZ. Unlike PRF, BVZ significantly increased the intratumor MMP2 and phospho-AKT (Ser473) levels coupled with the slight antiproliferative and significant antivascular effects. Co-administration of PRF and BVZ versus monotherapies potentiated the proapoptotic effects and reversed the BVZ-induced upregulation of phospho-AKT (Ser473) and MMP2 levels in C6 xenografts, leading to the optimal antiproliferative activity and tumor growth regression and longer survival. In conclusion, BVZ plus PRF renders a paramount proapoptotic effect, leading to a major therapeutic efficacy and might be a new substitute for GBM therapy in the clinic.
14.
Liu Y, Tang ZG, Lin Y, Qu XG, Lv W, Wang GB, Li CL.
Biomed Pharmacother. 2017 Aug;92:33-38. doi: 10.1016/j.biopha.2017.05.044. Epub 2017 May 18.
- Quercetin is a flavonoid that has been shown to have anti-oxidation, anti-inflammation, anti-allergic, anti-viral, and anti-cancer activities. Here, we examined the effects of quercetin on cell viability, cell cycle progression, and migration in U251 cells, a human glioblastoma cell line. We found that quercetin inhibited cell proliferation after treating cells for 24 (IC50 of 113.65μg/ml) or 48h (IC50 of 48.61μg/ml). Quercetin treatment also inducd apoptosis via deregulating the expression of apoptotic genes, including Bax and Bcl-2, and arrested cell cycle at G2/M phases. We further found that quercetin impaired cell migration and invasion via downregulating the expression of matrix metallopeptidases MMP9 and MMP2. Our results provide evidences that quercetin has inhibitory effects on glioblastoma cell proliferation and invasion, and suggest a potential clinical application for glioblastoma.
15.
Chen G, Yue Y, Qin J, Xiao X, Ren Q, Xiao B.
J Pharmacol Sci. 2017 May;134(1):59-67. doi: 10.1016/j.jphs.2017.04.003. Epub 2017 Apr 24.
- These findings suggest that the plumbagin-induced inhibition of glioma cell migration and invasion is closely associated with the downregulation of MMP-2/-9 expression and activity, and suppression of PI3K/Akt signaling pathway activation. Thus, plumbagin might be a potential anti-invasive agent in the treatment of glioma.
16.
Jain M, Harburn JJ, Gill JH, Loadman PM, Falconer RA, Mooney CA, Cobb SL, Berry DJ.
J Med Chem. 2017 May 25;60(10):4496-4502. doi: 10.1021/acs.jmedchem.6b01472. Epub 2017 May 10.
Matrix metalloproteinases
(MMPs) are central to cancer development and metastasis. They are
highly active in the tumor environment and absent or inactive in normal
tissues; therefore they represent viable targets for cancer drug
discovery. In this study we evaluated in silico docking to develop
MMP-subtype-selective tumor-activated prodrugs. Proof of principle for
this therapeutic approach was demonstrated in vitro against an
aggressive human glioma model, with involvement of MMPs confirmed using pharmacological inhibition.
17.
Walter C, Crawford L, Lai M, Toonen JA, Pan Y, Sakiyama-Elbert S, Gutmann DH, Pathak A.
Biophys J. 2017 Apr 25;112(8):1535-1538. doi: 10.1016/j.bpj.2017.03.017.
18.
Hu Y, Li Y, Wu C, Zhou L, Han X, Wang Q, Xie X, Zhou Y, Du Z.
Tumour Biol. 2017 Apr;39(4):1010428317697558. doi: 10.1177/1010428317697558.
- These findings suggested that miR-140-5p inhibited glioma proliferation and invasion by regulating the vascular endothelial growth factor A/matrix metalloproteinase-2 signaling pathway both in vitro and in vivo.
19.
Tezcan G, Taskapilioglu MO, Tunca B, Bekar A, Demirci H, Kocaeli H, Aksoy SA, Egeli U, Cecener G, Tolunay S.
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20.
Suzuki Y, Fujioka K, Ikeda K, Murayama Y, Manome Y.
J Clin Neurosci. 2017 Jul;41:144-149. doi: 10.1016/j.jocn.2017.03.048. Epub 2017 Apr 10.
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