This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Elkin, M. Articles by Vlodavsky, I. Search for Related Content PubMed PubMed Citation Articles by Elkin, M. Articles by Vlodavsky, I.

Inhibition of Matrix Metalloproteinase-2 Expression and Bladder Carcinoma Metastasis by Halofuginone¹

Departments of Oncology [M. E., E. A., I. V.], Pharmacology [R. R.], and Bone Marrow Transplantation [A. N.], Hadassah-Hebrew University Hospital, Jerusalem 91120; Department of Biological Chemistry, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904 [M. E., N. d-G., A. H.]; and Institute of Animal Science, the Volcany Center, Bet Dagan 50250 [M. P.], Israel

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 1 (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.

This article has been cited by other articles:

				L. K. McLoon Focusing on fibrosis: halofuginone-induced functional improvement in the mdx mouse model of Duchenne muscular dystrophy Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1505 - H1507. [Full Text] [PDF]

				M. Leiba, L. Cahalon, A. Shimoni, O. Lider, A. Zanin-Zhorov, I. Hecht, U. Sela, I. Vlodavsky, and A. Nagler Halofuginone inhibits NF-{kappa}B and p38 MAPK in activated T cells J. Leukoc. Biol., August 1, 2006; 80(2): 399 - 406. [Abstract] [Full Text] [PDF]

				Y. Popov, E. Patsenker, M. Bauer, E. Niedobitek, A. Schulze-Krebs, and D. Schuppan Halofuginone Induces Matrix Metalloproteinases in Rat Hepatic Stellate Cells via Activation of p38 and NF{kappa}B J. Biol. Chem., June 2, 2006; 281(22): 15090 - 15098. [Abstract] [Full Text] [PDF]

				E. Edovitsky, M. Elkin, E. Zcharia, T. Peretz, and I. Vlodavsky Heparanase Gene Silencing, Tumor Invasiveness, Angiogenesis, and Metastasis J Natl Cancer Inst, August 18, 2004; 96(16): 1219 - 1230. [Abstract] [Full Text] [PDF]

				S. Xavier, E. Piek, M. Fujii, D. Javelaud, A. Mauviel, K. C. Flanders, A. M. Samuni, A. Felici, M. Reiss, S. Yarkoni, et al. Amelioration of Radiation-induced Fibrosis: INHIBITION OF TRANSFORMING GROWTH FACTOR-{beta} SIGNALING BY HALOFUGINONE J. Biol. Chem., April 9, 2004; 279(15): 15167 - 15176. [Abstract] [Full Text] [PDF]

				D. J. Gross, I. Reibstein, L. Weiss, S. Slavin, H. Dafni, M. Neeman, M. Pines, and A. Nagler Treatment with Halofuginone Results in Marked Growth Inhibition of a von Hippel-Lindau Pheochromocytoma in Vivo Clin. Cancer Res., September 1, 2003; 9(10): 3788 - 3793. [Abstract] [Full Text] [PDF]

				O. Goldshmidt, E. Zcharia, R. Abramovitch, S. Metzger, H. Aingorn, Y. Friedmann, V. Schirrmacher, E. Mitrani, and I. Vlodavsky Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis PNAS, July 23, 2002; 99(15): 10031 - 10036. [Abstract] [Full Text] [PDF]

				M. ELKIN, H.-Q. MIAO, A. NAGLER, E. AINGORN, R. REICH, I. HEMO, H.-L. DOU, M. PINES, and I. VLODAVSKY Halofuginone: a potent inhibitor of critical steps in angiogenesis progression FASEB J, December 1, 2000; 14(15): 2477 - 2485. [Abstract] [Full Text]