נגישות
menu      
חיפוש מתקדם
תחביר
חפש...
הספר "אוצר וולקני"
אודות
תנאי שימוש
ניהול
קהילה:
אסיף מאגר המחקר החקלאי
פותח על ידי קלירמאש פתרונות בע"מ -
Inhibition of matrix metalloproteinase-2 expression and bladder carcinoma metastasis by halofuginone
Year:
1999
Source of publication :
Clinical Cancer Research
Authors :
פינס, מרק
;
.
Volume :
5
Co-Authors:
Elkin, M., Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel, Department of Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel
Reich, R., Department of Pharmacology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel
Nagler, A., Bone Marrow Transplantation, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel
Aingorn, E., Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel
Pines, M., Institute of Animal Science, Volcany Center, Bet Dagan 50250, Israel
De-Groot, N., Department of Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel
Hochberg, A., Department of Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel
Vlodavsky, I., Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel, Department of Oncology, Hadassah Hospital, P. O. Box 12000, Jerusalem, 91120, Israel
Facilitators :
From page:
1982
To page:
1988
(
Total pages:
7
)
Abstract:
Matrix metalloproteinase-2 (MMP-2) plays a critical role in tumor cell invasion and metastasis. Inhibitors of this enzyme effectively suppress tumor metastasis in experimental animals and are currently being tested in clinical trials. MMP-2 transcriptional regulation is a part of a delicate balance between the expression of various extracellular matrix (ECM) constituents and ECM degrading enzymes. Halofuginone, a low-molecular-weight quinazolinone alkaloid, is a potent inhibitor of collagen type α1 (I) gene expression and ECM deposition. We now report that expression of the MMP-2 gene by murine (MBT2-t50) and human (5637) bladder carcinoma cells is highly susceptible to inhibition by halofuginone. Fifty percent inhibition was obtained in the presence of as little as 50 ng/ml halofuginone. This inhibition is due to an effect of halofuginone on the activity of the MMP-2 promoter, as indicated by a pronounced suppression of chloramphenicol acetyltransferase activity driven by the MMP-2 promoter in transfected MBT2 cells. There was no effect on chloramphenicol acetyltransferase activity driven by SV40 promoter in these cells. Halofuginone-treated cells failed to invade through reconstituted basement-membrane (Matrigel) coated filters, in accordance with the inhibition of MMP-2 gene expression. A marked reduction (80-90%) in the lung colonization of MBT2 bladder carcinoma cells was obtained after the i.v. inoculation of halofuginone-treated cells as compared with the high metastatic activity exhibited by control untreated cells. Under the same conditions, there was almost no effect of halofuginone on the rate of MBT2 cell proliferation. These results indicate that the potent antimetastatic activity of halofuginone is due primarily to a transcriptional suppression of the MMP-2 gene, which results in a decreased enzymatic activity, matrix degradation, and tumor cell extravasation. This is the first description, to our knowledge, of a drug that inhibits experimental metastasis through the inhibition of MMP-2 at the transcriptional level. Combined with its known inhibitory effect on collagen synthesis and ECM deposition, halofuginone is expected to exert a profound anticancerous effect by inhibiting both the primary tumor stromal support and metastatic spread.
Note:
Related Files :
animal cell
Animals
carcinoma
cell invasion
human cell
mice
quinazolinone derivative
עוד תגיות
תוכן קשור
More details
DOI :
Article number:
Affiliations:
Database:
סקופוס
Publication Type:
מאמר
;
.
Language:
אנגלית
Editors' remarks:
ID:
20095
Last updated date:
02/03/2022 17:27
Creation date:
16/04/2018 23:34
Scientific Publication
Inhibition of matrix metalloproteinase-2 expression and bladder carcinoma metastasis by halofuginone
5
Elkin, M., Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel, Department of Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel
Reich, R., Department of Pharmacology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel
Nagler, A., Bone Marrow Transplantation, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel
Aingorn, E., Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel
Pines, M., Institute of Animal Science, Volcany Center, Bet Dagan 50250, Israel
De-Groot, N., Department of Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel
Hochberg, A., Department of Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel
Vlodavsky, I., Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel, Department of Oncology, Hadassah Hospital, P. O. Box 12000, Jerusalem, 91120, Israel
Inhibition of matrix metalloproteinase-2 expression and bladder carcinoma metastasis by halofuginone
Matrix metalloproteinase-2 (MMP-2) plays a critical role in tumor cell invasion and metastasis. Inhibitors of this enzyme effectively suppress tumor metastasis in experimental animals and are currently being tested in clinical trials. MMP-2 transcriptional regulation is a part of a delicate balance between the expression of various extracellular matrix (ECM) constituents and ECM degrading enzymes. Halofuginone, a low-molecular-weight quinazolinone alkaloid, is a potent inhibitor of collagen type α1 (I) gene expression and ECM deposition. We now report that expression of the MMP-2 gene by murine (MBT2-t50) and human (5637) bladder carcinoma cells is highly susceptible to inhibition by halofuginone. Fifty percent inhibition was obtained in the presence of as little as 50 ng/ml halofuginone. This inhibition is due to an effect of halofuginone on the activity of the MMP-2 promoter, as indicated by a pronounced suppression of chloramphenicol acetyltransferase activity driven by the MMP-2 promoter in transfected MBT2 cells. There was no effect on chloramphenicol acetyltransferase activity driven by SV40 promoter in these cells. Halofuginone-treated cells failed to invade through reconstituted basement-membrane (Matrigel) coated filters, in accordance with the inhibition of MMP-2 gene expression. A marked reduction (80-90%) in the lung colonization of MBT2 bladder carcinoma cells was obtained after the i.v. inoculation of halofuginone-treated cells as compared with the high metastatic activity exhibited by control untreated cells. Under the same conditions, there was almost no effect of halofuginone on the rate of MBT2 cell proliferation. These results indicate that the potent antimetastatic activity of halofuginone is due primarily to a transcriptional suppression of the MMP-2 gene, which results in a decreased enzymatic activity, matrix degradation, and tumor cell extravasation. This is the first description, to our knowledge, of a drug that inhibits experimental metastasis through the inhibition of MMP-2 at the transcriptional level. Combined with its known inhibitory effect on collagen synthesis and ECM deposition, halofuginone is expected to exert a profound anticancerous effect by inhibiting both the primary tumor stromal support and metastatic spread.
Scientific Publication
You may also be interested in